Drug Information

Drug (ID: DG00273) and It's Reported Resistant Information

• Name: Cisplatin
• Synonyms: Abiplatin; Biocisplatinum; Briplatin; Cismaplat; Cisplatine; Cisplatino; Cisplatinum; Cisplatyl; Citoplationo; Lederplatin; Neoplatin; Plastin; Platamine; Platidiam; Platinoxan; Randa; Cis-DDP; Cis-Diamminedichloroplatinum; Peyrone's chloride; Peyrone's salt; Cis-Dichlorodiammineplatinum(II); Cis-[PtCl2(NH3)2]; Cis-diamminedichloridoplatinum(II); Trans-diamminedichloridoplatinum(II); (SP-4-1)-diamminedichloridoplatinum; (SP-4-1)-diamminedichloroplatinum; (SP-4-2)-diamminedichloridoplatinum; (SP-4-2)-diamminedichloroplatinum; Cisplatin (Chemotherapy)
• Indication:
  In total 2 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1], [2], [3]
  Osteosarcoma [ICD-11: 2B51]; Phase 2; [1], [2], [3]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (27 diseases)
  Bladder cancer [ICD-11: 2C94]; [4]
  Brain cancer [ICD-11: 2A00]; [5]
  Breast cancer [ICD-11: 2C60]; [6]
  Cervical cancer [ICD-11: 2C77]; [6]
  Colorectal cancer [ICD-11: 2B91]; [7]
  Epithelial ovarian cancer [ICD-11: 2B5D]; [6]
  Esophageal cancer [ICD-11: 2B70]; [8]
  Gastric cancer [ICD-11: 2B72]; [9]
  Germ cell tumor [ICD-11: 2D12]; [10]
  Head and neck cancer [ICD-11: 2D42]; [11]
  HPV-related cervical cancer [ICD-11: 2E67]; [12]
  Kidney cancer [ICD-11: 2C90]; [13]
  Laryngeal cancer [ICD-11: 2C23]; [14]
  Liver cancer [ICD-11: 2C12]; [15]
  Lung cancer [ICD-11: 2C25]; [16]
  Mature T-cell lymphoma [ICD-11: 2A90]; [17]
  Melanoma [ICD-11: 2C30]; [18]
  Nasopharyngeal cancer [ICD-11: 2B6B]; [19]
  Oesophagogastric cancer [ICD-11: 2B71]; [20]
  Oral squamous cell carcinoma [ICD-11: 2B6E]; [21]
  Osteosarcoma [ICD-11: 2B51]; [22]
  Ovarian cancer [ICD-11: 2C73]; [23]
  Peripheral nerve sheath tumor [ICD-11: 2F3Y]; [24]
  Pleural mesothelioma [ICD-11: 2C26]; [25]
  Prostate cancer [ICD-11: 2C82]; [26]
  Rectal cancer [ICD-11: 2B92]; [27]
  Tongue cancer [ICD-11: 2B62]; [28]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (23 diseases)
  Bladder cancer [ICD-11: 2C94]; [29]
  Brain cancer [ICD-11: 2A00]; [30]
  Breast cancer [ICD-11: 2C60]; [31]
  Cervical cancer [ICD-11: 2C77]; [32]
  Colon cancer [ICD-11: 2B90]; [33]
  Endometrial cancer [ICD-11: 2C76]; [32]
  Epithelial ovarian cancer [ICD-11: 2B5D]; [34]
  Esophageal cancer [ICD-11: 2B70]; [35]
  Gastric cancer [ICD-11: 2B72]; [36]
  Laryngeal cancer [ICD-11: 2C23]; [37]
  Liver cancer [ICD-11: 2C12]; [38]
  Lung cancer [ICD-11: 2C25]; [39]
  Melanoma [ICD-11: 2C30]; [40]
  Nasopharyngeal cancer [ICD-11: 2B6B]; [41]
  Oral squamous cell carcinoma [ICD-11: 2B6E]; [42]
  Osteosarcoma [ICD-11: 2B51]; [43]
  Ovarian cancer [ICD-11: 2C73]; [44]
  Pancreatic cancer [ICD-11: 2C10]; [45]
  Prostate cancer [ICD-11: 2C82]; [46]
  Sarcoma [ICD-11: 2C35]; [47]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [48]
  Testicular cancer [ICD-11: 2C80]; [49]
  Tongue cancer [ICD-11: 2B62]; [50]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [2]
• Formula: Cl2H6N2Pt
• IsoSMILES: N.N.Cl[Pt]Cl
• InChI: 1S/2ClH.2H3N.Pt/h2*1H;2*1H3;/q;;;;+2/p-2
• InChIKey: LXZZYRPGZAFOLE-UHFFFAOYSA-L
• PubChem CID: 5702198
• TTD Drug ID: D0U5HU
• DrugBank ID: DB00515

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-520f [51]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both Sk-N-AsCis24 and in parental Sk-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in Sk-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in postchemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting.

Key Molecule: hsa-let-7f-1 [52]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: D425 cells; Brain; Homo sapiens (Human); CVCL_1275
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: High-Mobility Group Box 1 (HMGB1) is a direct target of miR-let-7f-1. HMGB1 is a highly conserved nuclear protein that functions as a chromatin-binding factor that bends DNA and promotes access to transcriptional protein assemblies on specific DNA targets. Overexpression of HMGB1 in cells treated with pSP and cisplatin blocked SPARC-induced cisplatin resistance indicating that overexpression of miR-let-7f-1 and a reduction in HMGB1 protein levels result in cellular resistance to cisplatin in SPARC over expressed cells. Earlier studies demonstrated that HMGB1 functions as a regulator of the balance between autophagy and apoptosis.

Key Molecule: hsa-let-7b [53]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell cycle; Inhibition; hsa04110
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression, resulting in resistance to cisplatin.

Key Molecule: hsa-mir-21 [30]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: BE(2) -M17 cells; Brain; Homo sapiens (Human); CVCL_0167
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Increased miR-21 expression might suppress the PTEN expression and eventually induce chemoresistance to cisplatin and increase cell proliferation.

Key Molecule: hsa-mir-204 [54]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Knockdown of LncRNA HOXD-AS1 suppresses proliferation, migration and invasion and enhances cisplatin sensitivity of glioma cells by sponging miR-20.

Key Molecule: HOXD antisense growth-associated long non-coding RNA (HAGLR) [54]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Knockdown of LncRNA HOXD-AS1 suppresses proliferation, migration and invasion and enhances cisplatin sensitivity of glioma cells by sponging miR-20.

Key Molecule: hsa-miR-214-3p [55]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pediatric intracranial nongerminomatous malignant germ cell tumors [ICD-11: 2A00.07]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT Assay
• Mechanism Description: miR214-3p overexpression enhanced cisplatin resistance by downregulating the expression of its target, the apoptotic protein BCL2-like 11 (BCL2L11/BIM).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: Cisplatin and etoposide are both substrates for membrane-bound efflux pumps, such as MRP and MDR1, which prevent their entry into the extracellular space of the central nervous system. The low levels of in vitro drug resistance noted for cisplatin and etoposide may be explained in part by the absence of such a barrier in our in vitro assay system.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 1 (BIRC1) [51]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both Sk-N-AsCis24 and in parental Sk-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in Sk-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in postchemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting.

Key Molecule: High mobility group protein B1 (HMGB1) [52]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: D425 cells; Brain; Homo sapiens (Human); CVCL_1275
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: High-Mobility Group Box 1 (HMGB1) is a direct target of miR-let-7f-1. HMGB1 is a highly conserved nuclear protein that functions as a chromatin-binding factor that bends DNA and promotes access to transcriptional protein assemblies on specific DNA targets. Overexpression of HMGB1 in cells treated with pSP and cisplatin blocked SPARC-induced cisplatin resistance indicating that overexpression of miR-let-7f-1 and a reduction in HMGB1 protein levels result in cellular resistance to cisplatin in SPARC over expressed cells. Earlier studies demonstrated that HMGB1 functions as a regulator of the balance between autophagy and apoptosis.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [53]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression, resulting in resistance to cisplatin.

Key Molecule: Phosphatase and tensin homolog (PTEN) [30]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: BE(2) -M17 cells; Brain; Homo sapiens (Human); CVCL_0167
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Increased miR-21 expression might suppress the PTEN expression and eventually induce chemoresistance to cisplatin and increase cell proliferation.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [55]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pediatric intracranial nongerminomatous malignant germ cell tumors [ICD-11: 2A00.07]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Immunoblotting assay; Immunohistochemistry
• Experiment for Drug Resistance: MTT Assay
• Mechanism Description: miR214-3p overexpression enhanced cisplatin resistance by downregulating the expression of its target, the apoptotic protein BCL2-like 11 (BCL2L11/BIM).

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-141 [56]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the IMR-32 and SH-SY5Y cells, lentivirus-induced miR-141 upregulation inhibited cancer proliferation, cell cycle progression, migration and increased cisplatin chemosensitivity in vitro. In addition, miR-141 upregulation reduced the in vivo growth of IMR-32 tumor explants. FUS was found to be inversely regulated by miR-141 in NB. Small interfering RNA (siRNA)-induced FUS downregulation had similar tumor-suppressive effects as miR-141 upregulation on NB cell proliferation, cell cycle progression, migration and cisplatin chemosensitivity.

Key Molecule: hsa-mir-873 [57]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bcl-2 was a direct target of miR 873, and miR 873 decreased the level of the Bcl-2 protein in cisplatin-resistant glioma cells. Notably, re-expression of Bcl-2 attenuated the function of miR 873 in cisplatin-resistant glioma cells and the sensitivity of the cells to cisplatin.

Key Molecule: hsa-mir-30d [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-204 [59]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: hsa-mir-34 [60]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: hsa-mir-204 [54]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: miR-204 overexpression suppressed proliferation, migration and invasion and enhanced the DDP sensitivity in glioma cells.

Key Molecule: Maternally expressed 3 (MEG3) [61]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long non coding RNA MEG3 contributes to cisplatin induced apoptosis via inhibition of autophagy in human glioma cells.

Key Molecule: Long non-protein coding RNA (AC023115.3) [62]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR26a/GSk3Beta/Mcl1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC staining assay; Flow cytometry assay
• Mechanism Description: AC023115.3 sensitized glioma cell to cisplatin-induced apoptosis through regulation of the miR26a-GSk3beta-Mcl1 signalling. AC023115.3 acted as a miR26a sponge and inhibited its activity, thus increased the expression of GSk3beta.

Key Molecule: hsa-mir-26a [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: miR26a/GSk3Beta/Mcl1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC staining assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA AC023115.3 suppresses chemoresistance of glioblastoma by reducing autophagy. AC023115.3 acts as a competing endogenous RNA for miR26a and attenuates the inhibitory effect of miR26a on GSk3beta, leading to an increase in GSk3beta and a decrease in autophagy.

Key Molecule: hsa-mir-186 [63]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 186 reverses cisplatin resistance and inhibits the formation of the GIC phenotype by degrading YY1 in glioblastoma.

Key Molecule: hsa-miR-501-3p [64]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-501-3p sensitizes glioma cells to cisplatin via reducing protein levels of MYCN.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: RNA-binding protein FUS (FUS) [56]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the IMR-32 and SH-SY5Y cells, lentivirus-induced miR-141 upregulation inhibited cancer proliferation, cell cycle progression, migration and increased cisplatin chemosensitivity in vitro. In addition, miR-141 upregulation reduced the in vivo growth of IMR-32 tumor explants. FUS was found to be inversely regulated by miR-141 in NB. Small interfering RNA (siRNA)-induced FUS downregulation had similar tumor-suppressive effects as miR-141 upregulation on NB cell proliferation, cell cycle progression, migration and cisplatin chemosensitivity.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [57]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bcl-2 was a direct target of miR 873, and miR 873 decreased the level of the Bcl-2 protein in cisplatin-resistant glioma cells. Notably, re-expression of Bcl-2 attenuated the function of miR 873 in cisplatin-resistant glioma cells and the sensitivity of the cells to cisplatin.

Key Molecule: Beclin-1 (BECN1) [58]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [59]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: BDNF/NT-3 growth factors receptor (NTRK2) [59]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: Melanoma-associated antigen 12 (MAGEA12) [60]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 2 (MAGEA2) [60]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 3 (MAGEA3) [60]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 6 (MAGEA6) [60]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [62]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR26a/GSk3Beta/Mcl1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC staining assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA AC023115.3 suppresses chemoresistance of glioblastoma by reducing autophagy. AC023115.3 acts as a competing endogenous RNA for miR26a and attenuates the inhibitory effect of miR26a on GSk3beta, leading to an increase in GSk3beta and a decrease in autophagy.

Key Molecule: Transcriptional repressor protein YY1 (TYY1) [63]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 186 reverses cisplatin resistance and inhibits the formation of the GIC phenotype by degrading YY1 in glioblastoma.

Key Molecule: N-myc proto-oncogene protein (MYCN) [64]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-501-3p sensitizes glioma cells to cisplatin via reducing protein levels of MYCN.

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: TP53 target 1 (TP53TG1) [48]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: GCIY cells; Gastric; Homo sapiens (Human); CVCL_1228
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: MkN-7 cells; Gastric; Homo sapiens (Human); CVCL_1417
• In Vitro Model: SNU-1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: TGBC11TkB cells; Gastric; Homo sapiens (Human); CVCL_1768
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
• Mechanism Description: TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Y-box-binding protein 1 (YBX1) [48]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: GCIY cells; Gastric; Homo sapiens (Human); CVCL_1228
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: MkN-7 cells; Gastric; Homo sapiens (Human); CVCL_1417
• In Vitro Model: SNU-1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: TGBC11TkB cells; Gastric; Homo sapiens (Human); CVCL_1768
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
• Mechanism Description: TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.

Mature T-cell lymphoma [ICD-11: 2A90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [17]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MOLT4 cells; Bone marrow; Homo sapiens (Human); CVCL_0013
• In Vitro Model: HUT78 cells; Lymph; Homo sapiens (Human); CVCL_0337
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERk) and AkT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Maternally expressed 3 (MEG3) [65]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Peripheral T-cell lymphoma [ICD-11: 2A90.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: SUP-T1 cells; Pleural effusion; Homo sapiens (Human); CVCL_1714
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: MEG3 promotes the drug sensitivity of T-LBL to chemotherapeutic agents by affecting the PI3k/mTOR pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: WT1 associated protein (WTAP) [66]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Natural killer/T-cell lymphoma [ICD-11: 2A90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: YTS cells; Pleural effusion; Homo sapiens (Human); CVCL_D324
• In Vitro Model: SNK-6 cells; Oral; Homo sapiens (Human); CVCL_A673
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: WTAP enhanced dual-specificity phosphatases 6 (DUSP6) expression by increasing m6A levels of DUSP6 mRNA transcript, leading to oncogenic functions in NKTCL. WTAP contributed to the progression and chemotherapy sensitivity of NKTCL by stabilizing DUSP6 mRNA in an m6A-dependent manner. Taken together, these findings uncovered a critical function for WTAP-guided m6A methylation and identified DUSP6 as an important target of m6A modification in the regulation of chemotherapy resistance in NKTCL oncogenesis. Deletion of WTAP impaired chemotherapy resistance to DDP in human NKTCL cells.

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-138 [67]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [67]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Chondrosarcoma [ICD-11: 2B50]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-100 [68]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chondrosarcoma [ICD-11: 2B50.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: C-28/l2 cells; Cartilage; Homo sapiens (Human); CVCL_0187
• In Vitro Model: CHON-001 cells; Cartilage; Homo sapiens (Human); CVCL_C462
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: mTOR is frequently activated in multiple carcinoma. The overexpression of miR-100 significantly down-regulated mTOR proteins and inhibition of miR-100 restored the expression of mTOR in CH-2879 cells, the present studies highlight miR-100 as a tumor suppressor in chondrosarcoma contributing to anti-chemoresistance.

Key Molecule: hsa-mir-23b [69]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chondrosarcoma [ICD-11: 2B50.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Src/AKT signaling pathway; Inhibition; hsa04917
• In Vitro Model: CH-2879 cells; Bone; Homo sapiens (Human); CVCL_9921
• In Vitro Model: OUMS-27 cells; Bone; Homo sapiens (Human); CVCL_3090
• In Vitro Model: SW1353 cells; Bone; Homo sapiens (Human); CVCL_0543
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: Src kinase is a direct target of miR23b in chondrosarcoma cells, overexpression of miR23b suppresses Src-Akt pathway, leading to the sensitization of cisplatin resistant chondrosarcoma cells to cisplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [68]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chondrosarcoma [ICD-11: 2B50.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: C-28/l2 cells; Cartilage; Homo sapiens (Human); CVCL_0187
• In Vitro Model: CHON-001 cells; Cartilage; Homo sapiens (Human); CVCL_C462
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: mTOR is frequently activated in multiple carcinoma. The overexpression of miR-100 significantly down-regulated mTOR proteins and inhibition of miR-100 restored the expression of mTOR in CH-2879 cells, the present studies highlight miR-100 as a tumor suppressor in chondrosarcoma contributing to anti-chemoresistance.

Key Molecule: Proto-oncogene tyrosine-protein kinase Src (SRC) [69]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chondrosarcoma [ICD-11: 2B50.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Src/AKT signaling pathway; Inhibition; hsa04917
• In Vitro Model: CH-2879 cells; Bone; Homo sapiens (Human); CVCL_9921
• In Vitro Model: OUMS-27 cells; Bone; Homo sapiens (Human); CVCL_3090
• In Vitro Model: SW1353 cells; Bone; Homo sapiens (Human); CVCL_0543
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: Src kinase is a direct target of miR23b in chondrosarcoma cells, overexpression of miR23b suppresses Src-Akt pathway, leading to the sensitization of cisplatin resistant chondrosarcoma cells to cisplatin.

Osteosarcoma [ICD-11: 2B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34a-5p [70]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MEF2 signaling pathway; Regulation; hsa04013
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.

Key Molecule: hsa-miR-146b-5p [43]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: hFOB1.19 cells; Fetal bone; Homo sapiens (Human); CVCL_3708
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.

Key Molecule: hsa-mir-33a [71]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST.

Key Molecule: hsa-mir-221 [22]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: SOSP-9607 cells; Bones; Homo sapiens (Human); CVCL_4V80
• In Vitro Model: SOSP-9901 cells; Bones; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-221 induce cell survival and cisplatin resistance in human osteosarcoma at least partly through targeting the PI3k/PTEN/Akt pathway.

Key Molecule: OIP5 antisense RNA 1 (OIP5-AS1) [72]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: OIP5-AS1 regulates cisplatin resistance by activating the PI3k/AkT/mTOR signaling pathway.

Key Molecule: hsa-miR-340-5p [72]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: OIP5-AS1 regulates cisplatin resistance by activating the PI3k/AkT/mTOR signaling pathway.

Key Molecule: Delta-like protein 1 (DLL1) [73]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay; Flow cytometric analysis
• Mechanism Description: miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.

Key Molecule: hsa-miR-199a-3p [74]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [75]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BCL2/cyclin D1 signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.

Key Molecule: hsa-mir-377 [76]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MG63/CDDP cells; Bone; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2/CDDP cells; Bone; Homo sapiens (Human); CVCL_0548
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: XIAP overexpression greatly cancelled the apoptosis promoting the effect of miR377 in Saos-2/CDDP cell.

Key Molecule: hsa_circ_PVT1 [77]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: KHOS cells; Bone; Homo sapiens (Human); CVCL_2546
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: CircPVT1 knockdown reduces the expression of classical multidrug resistance related gene-ABCB1 in OS cells.

Key Molecule: hsa-mir-340 [78]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of ZEB1 reversed the miR-340-induced alleviation of chemoresistance in drug-resistant OS cells.

Key Molecule: hsa-miR-34a-5p [73], [79]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
• Mechanism Description: The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. And miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [77]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: KHOS cells; Bone; Homo sapiens (Human); CVCL_2546
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: CircPVT1 knockdown reduces the expression of classical multidrug resistance related gene-ABCB1 in OS cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) [80]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Ckk-8 assay; Colony formation assay; Annexin V-FITC staining assay
• Mechanism Description: Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR645-IFIT2 axis. LINC00161 upregulated IFIT2 expression via miR645.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [70]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MEF2 signaling pathway; Regulation; hsa04013
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.

Key Molecule: E3 ubiquitin-protein ligase ZNRF3 (ZNRF3) [43]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: hFOB1.19 cells; Fetal bone; Homo sapiens (Human); CVCL_3708
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/beta-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness.

Key Molecule: Twist-related protein 1 (TWST1) [71]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST.

Key Molecule: Phosphatase and tensin homolog (PTEN) [22]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: SOSP-9607 cells; Bones; Homo sapiens (Human); CVCL_4V80
• In Vitro Model: SOSP-9901 cells; Bones; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-221 induce cell survival and cisplatin resistance in human osteosarcoma at least partly through targeting the PI3k/PTEN/Akt pathway.

Key Molecule: Interleukin-24 (IL24) [81]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ZBTB7A/LINC00473/IL24 signaling pathway; Regulation; hsa04630
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR; Dual-Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LINC00473 promoted the activity of IL24 promoter and elevated IL24 expression. LINC00473 interacts with the transcript factor C/EBPbeta, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. The ZBTB7A-LINC00473-IL24 signaling axis plays an important role in regulating osteosarcoma chemoresistance.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [81]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ZBTB7A/LINC00473/IL24 signaling pathway; Regulation; hsa04630
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Elevated ZBTB7A inhibits cisplatin-induced apoptosis by repressing LINC00473 expression. The ZBTB7A-LINC00473-IL24 signaling axis plays an important role in regulating osteosarcoma chemoresistance.

Key Molecule: Type-1 angiotensin II receptor (AGTR1) [79]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
• Mechanism Description: The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.

Key Molecule: Adenylate kinase 4 (AK4) [74]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [75]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BCL2/cyclin D1 signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [75]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BCL2/cyclin D1 signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [76]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MG63/CDDP cells; Bone; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2/CDDP cells; Bone; Homo sapiens (Human); CVCL_0548
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: XIAP overexpression greatly cancelled the apoptosis promoting the effect of miR377 in Saos-2/CDDP cell.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [78]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of ZEB1 reversed the miR-340-induced alleviation of chemoresistance in drug-resistant OS cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-199a-5p [82]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR199a-5p directly targeted Beclin1 and negatively mediated Beclin1 expression at a post-transcriptional level, microRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells.

Key Molecule: hsa-miR-422a [83]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HFOB cells; Bone; Homo sapiens (Human); CVCL_3708
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis of apoptosis; Transwell assay
• Mechanism Description: Overexpression of miR422a inhibits cell proliferation and invasion, and enhances chemosensitivity by directly targeting TGFbeta2 in osteosarcoma cells.

Key Molecule: hsa-mir-381 [84]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Matrigel chamber invasion assay
• Mechanism Description: There is a strong negative correlation between the expression of miR381 and LRRC4, suppressing the expression of miR381 increases the sensitivity of OS cells to chemotherapeutic drugs through the LRRC4-mediated mTOR pathway.

Key Molecule: Long non-protein coding RNA 161 (LINC00161) [80]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Ckk-8 assay; Colony formation assay; Annexin V-FITC staining assay
• Mechanism Description: Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR645-IFIT2 axis. LINC00161 acted as a miR645 sponge and inhibited its activity.

Key Molecule: hsa-miR-645 [80]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Ckk-8 assay; Colony formation assay; Annexin V-FITC staining assay
• Mechanism Description: Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR645-IFIT2 axis. LINC00161 acted as a miR645 sponge and inhibited its activity.

Key Molecule: hsa-mir-21 [85]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vitro Model: HLNG cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Scratch assay
• Mechanism Description: miR-21 regulatory network plays a role in tumorigenesis of osteosarcoma. Its expression facilitates cell proliferation and decreases cellular sensitivity towards cisplatin. Both effects can be rescued by Spry2, a target protein downregulated by increased miR-21 levels.

Key Molecule: hsa-mir-138 [86]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR138/EZH2 signaling pathway; Regulation; hsa05206
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vivo Model: BALB/c nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-138 acts as a tumor suppressor in osteosarcoma, inhibiting cell proliferation, migration, and invasion by downregulating EZH2 expression. Mir-138 overexpression also enhances osteosarcoma cell chemosensitivity to cisplatin by targeting EZH2.

Key Molecule: hsa-mir-125b [87]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53/p38/MAPK signaling pathway; Regulation; hsa04010
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-125b inhibited proliferation, migration, and invasion of OS cells and reduced the chemotherapy resistance of OS cells to cisplatin by targeting Bcl-2.

Key Molecule: hsa-mir-382 [88]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.

Key Molecule: hsa-mir-29b [89]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AB-OS CSC cells; Bone marrow; Homo sapiens (Human); CVCL_LM95
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Trypan blue assay; Flow cytometry assay
• Mechanism Description: miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis miR-29b-1 negatively regulated the expression of Bcl-2.

Key Molecule: hsa-mir-103 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-mir-96 [91]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: hsa-mir-34 [92]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Bim signaling pathway; Activation; hsa05206
• Cell Pathway Regulation: c-Myc signaling pathway; Activation; hsa05230
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR34a increases cisplatin sensitivity of osteosarcoma cells in vitro through up-regulation of c-Myc and Bim signal.

Key Molecule: hsa-mir-200c [93]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Caspase-3 Activity Assay
• Mechanism Description: miR200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AkT2 and inhibiting the activity of cell proliferation and cell migration.

Key Molecule: Long non-protein coding RNA (LINC00473) [81]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ZBTB7A/LINC00473/IL24 signaling pathway; Regulation; hsa04630
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LINC00473 promoted the activity of IL24 promoter and elevated IL24 expression. LINC00473 interacts with the transcript factor C/EBPbeta, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. The ZBTB7A-LINC00473-IL24 signaling axis plays an important role in regulating osteosarcoma chemoresistance.

Key Molecule: hsa-mir-491 [94]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR491 inhibits chemoresistance and suppresses OS cell lung metastasis, whereas it enhances cisplatin (CDDP)-induced tumor growth inhibition and apoptosis, miR491 exerts its role by directly targeting alphaB-crystallin (CRYAB) in OS.

Key Molecule: hsa-miR-340-5p [95]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MG63/CDDP cells; Bone; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2/CDDP cells; Bone; Homo sapiens (Human); CVCL_0548
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC apoptosis assay
• Mechanism Description: microRNA-340-5p modulates cisplatin resistance by targeting LPAATbeta in osteosarcoma.

Key Molecule: hsa-mir-410 [96]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HFob 1.19; Bone; Homo sapiens (Human); CVCL_3708
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.

Key Molecule: CDKN2B antisense RNA 1 (CDKN2B-AS1) [97]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ANRIL-silenced cells were more sensitive to cisplatin and the expression level of miR-125a-5p was elevated in ANRIL-silenced cells.

Key Molecule: hsa-miR-125a-5p [97]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ANRIL-silenced cells were more sensitive to cisplatin and the expression level of miR-125a-5p was elevated in ANRIL-silenced cells.

Key Molecule: hsa-mir-92a [98]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Regulation; hsa04330
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: HFOB cells; Bone; Homo sapiens (Human); CVCL_3708
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: miR-92a inhibited cell growth, migration, and enhanced cisplatin sensitivity of OS cell by downregulating Notch1.

Key Molecule: hsa-mir-34c [75]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BCL2/cyclin D1 signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.

Key Molecule: hsa-mir-22 [99]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-22 overexpression sensitizes MG-63 cells to cisplatin treatment and reduces the expression of S100A11.

Key Molecule: hsa-mir-223 [100]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: JNk signaling pathway; Activation; hsa04010
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: Sk-ES-1 cells; Bone; Homo sapiens (Human); CVCL_0627
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-223 overexpression could sensitize OS cell lines to CDDP and Hsp70 protein levels were remarkably reduced by miR-223 overexpression whereas increased by miR-223 inhibition.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin-1 (BECN1) [82]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR199a-5p directly targeted Beclin1 and negatively mediated Beclin1 expression at a post-transcriptional level, microRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells.

Key Molecule: Transforming growth factor beta-2 proprotein (TGFB2) [83]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HFOB cells; Bone; Homo sapiens (Human); CVCL_3708
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase activity assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis of apoptosis; Transwell assay
• Mechanism Description: Overexpression of miR422a inhibits cell proliferation and invasion, and enhances chemosensitivity by directly targeting TGFbeta2 in osteosarcoma cells.

Key Molecule: Leucine-rich repeat-containing protein 4 (LRRC4) [84]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Matrigel chamber invasion assay
• Mechanism Description: There is a strong negative correlation between the expression of miR381 and LRRC4, suppressing the expression of miR381 increases the sensitivity of OS cells to chemotherapeutic drugs through the LRRC4-mediated mTOR pathway.

Key Molecule: Protein sprouty homolog 2 (SPRY2) [85]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vitro Model: HLNG cells; Bone marrow; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Northern blotting
• Experiment for Drug Resistance: Scratch assay
• Mechanism Description: miR-21 regulatory network plays a role in tumorigenesis of osteosarcoma. Its expression facilitates cell proliferation and decreases cellular sensitivity towards cisplatin. Both effects can be rescued by Spry2, a target protein downregulated by increased miR-21 levels.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [86]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR138/EZH2 signaling pathway; Regulation; hsa05206
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• Experiment for Molecule Alteration: Western blot analysis; Flow cytometric assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-138 acts as a tumor suppressor in osteosarcoma, inhibiting cell proliferation, migration, and invasion by downregulating EZH2 expression. Mir-138 overexpression also enhances osteosarcoma cell chemosensitivity to cisplatin by targeting EZH2.

Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3) [88]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.

Key Molecule: Krueppel-like factor 12 (KLF12) [88]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Decreased miR-382 was associated with poor survival in OS patients. Overexpression of miR-382 inhibited cell growth and chemoresistance by targeting kLF12 and HIPk3, respectively. In contrast, inhibition of miR-382 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: DNA repair protein REV1 (REV1) [91]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: RAC-beta serine/threonine-protein kinase (AKT2) [93]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Caspase-3 Activity Assay
• Mechanism Description: miR200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AkT2 and inhibiting the activity of cell proliferation and cell migration.

Key Molecule: Alpha-crystallin B chain (CRYAB) [94]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay; Western blot analysis; Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR491 inhibits chemoresistance and suppresses OS cell lung metastasis, whereas it enhances cisplatin (CDDP)-induced tumor growth inhibition and apoptosis, miR491 exerts its role by directly targeting alphaB-crystallin (CRYAB) in OS.

Key Molecule: Lysophosphatidic acid acyltransferase beta (AGPAT2) [95]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MG63/CDDP cells; Bone; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2/CDDP cells; Bone; Homo sapiens (Human); CVCL_0548
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC apoptosis assay
• Mechanism Description: microRNA-340-5p modulates cisplatin resistance by targeting LPAATbeta in osteosarcoma.

Key Molecule: Autophagy-related protein 16-1 (ATG16L1) [96]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HFob 1.19; Bone; Homo sapiens (Human); CVCL_3708
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma, miR410 directly decreased ATG16L1 expression by targeting its 3'-untranslated region.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [98]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Regulation; hsa04330
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: HFOB cells; Bone; Homo sapiens (Human); CVCL_3708
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: miR-92a inhibited cell growth, migration, and enhanced cisplatin sensitivity of OS cell by downregulating Notch1.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [75]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BCL2/cyclin D1 signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 143B cells; Bone; Homo sapiens (Human); CVCL_2270
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The miR-34c inhibitor restored the BCL-2 and cyclin D1 levels in MG63 and HOS cell line, which implicated that NEAT1 inhibited the tumor suppressor miR-34c and up-regulated cell survival signals for the development of OS.

Key Molecule: Protein S100-A11 (S100A11) [99]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-22 overexpression sensitizes MG-63 cells to cisplatin treatment and reduces the expression of S100A11.

Key Molecule: Heat shock 70 kDa protein 1A (HSP70) [100]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: JNk signaling pathway; Activation; hsa04010
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: Sk-ES-1 cells; Bone; Homo sapiens (Human); CVCL_0627
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-223 overexpression could sensitize OS cell lines to CDDP and Hsp70 protein levels were remarkably reduced by miR-223 overexpression whereas increased by miR-223 inhibition.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [87], [89]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53/p38/MAPK signaling pathway; Regulation; hsa04010
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HOS cells; Bone; Homo sapiens (Human); CVCL_0312
• In Vitro Model: 3AB-OS CSC cells; Bone marrow; Homo sapiens (Human); CVCL_LM95
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: Trypan blue assay; Flow cytometry assay; CCK8 assay
• Mechanism Description: miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis miR-29b-1 negatively regulated the expression of Bcl-2. Overexpression of miR-125b inhibited proliferation, migration, and invasion of OS cells and reduced the chemotherapy resistance of OS cells to cisplatin by targeting Bcl-2.

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [90], [91]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. And overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Epithelial ovarian cancer [ICD-11: 2B5D]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-100 [101]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Crystal violet staining assay
• Mechanism Description: miR100 resensitizes resistant epithelial ovarian cancer to cisplatin probably by inhibiting cell proliferation, inducing apoptosis and arresting cell cycle and by targeted downregulation of mTOR and PLk1 expression.

Key Molecule: hsa-mir-520g [102]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MAPK/AKT signaling pathway; Regulation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: MCAS cells; Ovary; Homo sapiens (Human); CVCL_3020
• In Vitro Model: OVk18 cells; Ovary; Homo sapiens (Human); CVCL_3770
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-520g expression is significantly increased in EOC and high miR-520g expression promotes tumor development, increases chemoresistance to platinum-based chemotherapy and reduces patient survival. miR-520g directly targets and downregulates DAPk2 by binding the DAPk2 3'UTR. DAPk2 suppression, followed by MAPk and AkT pathway activation, promotes the biological processes mediated by miR-520g in EOC.

Key Molecule: hsa-mir-136 [103]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Trypan blue staining assay; Flow cytometry assay
• Mechanism Description: miR-136 may function as an anti-oncogene and deficiency of miR-136 expression in ovarian cancer can induce chemoresistance at least in part by downregulating apoptosis and promoting the repair of cisplatin-induced DNA damage. Thus, miR-136 may provide a biomarker for predicting the chemosensitivity to cisplatin in patients with epithelial ovarian cancer.

Key Molecule: hsa-let-7e [34]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of let-7e by transfection of agomir could resensitize A2780/CP and reduce the expression of cisplatin-resistant-related proteins enhancer of zeste 2 (EZH2) and cyclin D1 (CCND1), whereas let-7e inhibitors increased resistance to cisplatin in parental A2780 cells.

Key Molecule: hsa-let-7i [6]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR10 cells; Ovary; Homo sapiens (Human); CVCL_4377
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reduced let-7i expression significantly increased the resistance of ovarian and breast cancer cells to the chemotherapy drug, cis-platinum.

Key Molecule: hsa-mir-363 [104]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Down-regulation of miR-363 led to cisplatin resistance in the epithelial ovarian cancer.

Key Molecule: hsa-mir-363 [104]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Down-regulation of miR-363 led to cisplatin resistance in the epithelial ovarian cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [101]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Crystal violet staining assay
• Mechanism Description: miR100 resensitizes resistant epithelial ovarian cancer to cisplatin probably by inhibiting cell proliferation, inducing apoptosis and arresting cell cycle and by targeted downregulation of mTOR and PLk1 expression.

Key Molecule: Serine/threonine-protein kinase PLK1 (PLK1) [101]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Crystal violet staining assay
• Mechanism Description: miR100 resensitizes resistant epithelial ovarian cancer to cisplatin probably by inhibiting cell proliferation, inducing apoptosis and arresting cell cycle and by targeted downregulation of mTOR and PLk1 expression.

Key Molecule: Death-associated protein kinase 2 (DAPK2) [102]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MAPK/AKT signaling pathway; Regulation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: MCAS cells; Ovary; Homo sapiens (Human); CVCL_3020
• In Vitro Model: OVk18 cells; Ovary; Homo sapiens (Human); CVCL_3770
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-520g expression is significantly increased in EOC and high miR-520g expression promotes tumor development, increases chemoresistance to platinum-based chemotherapy and reduces patient survival. miR-520g directly targets and downregulates DAPk2 by binding the DAPk2 3'UTR. DAPk2 suppression, followed by MAPk and AkT pathway activation, promotes the biological processes mediated by miR-520g in EOC.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Spheroid formation; Activation; hsa04140
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of let-7e by transfection of agomir could resensitize A2780/CP and reduce the expression of cisplatin-resistant-related proteins enhancer of zeste 2 (EZH2) and cyclin D1 (CCND1), whereas let-7e inhibitors increased resistance to cisplatin in parental A2780 cells.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of let-7e by transfection of agomir could resensitize A2780/CP and reduce the expression of cisplatin-resistant-related proteins enhancer of zeste 2 (EZH2) and cyclin D1 (CCND1), whereas let-7e inhibitors increased resistance to cisplatin in parental A2780 cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-424 [105]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: CD80/CTLA-4 signaling pathway; Regulation; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: T-cell apoptosis assay
• Mechanism Description: High expression levels of miR-424(322) were positively correlated with the PFS of ovarian cancer patients. miR-424(322) overexpression reduced PD-L1 and CD80 expression through direct binding to the 3'-UTR of these genes. Furthermore, low miR-424(322) and high PD-L1 expression were significantly correlated and strongly associated with chemoresistant phenotypes in ovarian cancer cells and tissues. Restoration of miR-424(322) expression (+) the sensitivity of cancer cells to drug treatment and was accompanied by T-cell activation by blocking the PD-L1 immune checkpoint in both in vitro and in vivo models. Our current findings indicate that miR-424(322) regulates PD-L1 and CD80 expression. Therefore, miR-424(322) might serve as a therapeutic target to enhance the chemosensitivity of ovarian cancer cells through checkpoint blockage, which thereby promotes the T-cell response in attacking tumour cells.

Key Molecule: hsa-miR-509-3p [106]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-509-3p can not only downregulate the expression of XIAP in ovarian cancer cells but also inhibit the proliferation of EOC cells and increase their sensitivity to cisplatin-induced apoptosis.

Key Molecule: hsa-mir-101 [107]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU assay
• Mechanism Description: miR-101 overexpression decreased the expression of EZH2, reduced proliferation and migration of ovarian cancer cells, and resensitized drug-resistant cancer cells to cisplatin-induced cytotoxicity.

Key Molecule: Growth arrest specific 5 (GAS5) [108]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell formation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Regulation; hsa04010
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: GAS5 might regulate PARP1 expression by recruiting the transcription factor E2F4 to its promoter, and then affect the MAPk pathway activity and enhance sensitivity to DDP of OC both in vitro and in vivo.

Key Molecule: hsa-miR-429 [109]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
• Mechanism Description: Down-regulation of miR429 contributes to the development of drug resistance in epithelial ovarian cancer by targeting ZEB1.

Key Molecule: hsa-let-7e [110]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Colony-formation assay
• Mechanism Description: Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing RNA double strand break repair In EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance.

Key Molecule: hsa-miR-214-3p [111]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulation of long non-coding RNA XIST has anticancer effects on epithelial ovarian cancer cells through inverse downregulation of hsa-miR-214-3p.

Key Molecule: X inactive specific transcript (XIST) [111]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulation of long non-coding RNA XIST has anticancer effects on epithelial ovarian cancer cells through inverse downregulation of hsa-miR-214-3p.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: T-lymphocyte activation antigen CD80 (CD80) [105]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PD-L1/PD-1 signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: T-cell apoptosis assay
• Mechanism Description: High expression levels of miR-424(322) were positively correlated with the PFS of ovarian cancer patients. miR-424(322) overexpression reduced PD-L1 and CD80 expression through direct binding to the 3'-UTR of these genes. Furthermore, low miR-424(322) and high PD-L1 expression were significantly correlated and strongly associated with chemoresistant phenotypes in ovarian cancer cells and tissues. Restoration of miR-424(322) expression (+) the sensitivity of cancer cells to drug treatment and was accompanied by T-cell activation by blocking the PD-L1 immune checkpoint in both in vitro and in vivo models. Our current findings indicate that miR-424(322) regulates PD-L1 and CD80 expression. Therefore, miR-424(322) might serve as a therapeutic target to enhance the chemosensitivity of ovarian cancer cells through checkpoint blockage, which thereby promotes the T-cell response in attacking tumour cells.

Key Molecule: T-lymphocyte activation antigen CD80 (CD80) [105]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: CD80/CTLA-4 signaling pathway; Regulation; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: T-cell apoptosis assay
• Mechanism Description: High expression levels of miR-424(322) were positively correlated with the PFS of ovarian cancer patients. miR-424(322) overexpression reduced PD-L1 and CD80 expression through direct binding to the 3'-UTR of these genes. Furthermore, low miR-424(322) and high PD-L1 expression were significantly correlated and strongly associated with chemoresistant phenotypes in ovarian cancer cells and tissues. Restoration of miR-424(322) expression (+) the sensitivity of cancer cells to drug treatment and was accompanied by T-cell activation by blocking the PD-L1 immune checkpoint in both in vitro and in vivo models. Our current findings indicate that miR-424(322) regulates PD-L1 and CD80 expression. Therefore, miR-424(322) might serve as a therapeutic target to enhance the chemosensitivity of ovarian cancer cells through checkpoint blockage, which thereby promotes the T-cell response in attacking tumour cells.

Key Molecule: Cytotoxic T-lymphocyte protein 4 (CTLA4) [105]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: CD80/CTLA-4 signaling pathway; Regulation; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: T-cell apoptosis assay
• Mechanism Description: High expression levels of miR-424(322) were positively correlated with the PFS of ovarian cancer patients. miR-424(322) overexpression reduced PD-L1 and CD80 expression through direct binding to the 3'-UTR of these genes. Furthermore, low miR-424(322) and high PD-L1 expression were significantly correlated and strongly associated with chemoresistant phenotypes in ovarian cancer cells and tissues. Restoration of miR-424(322) expression (+) the sensitivity of cancer cells to drug treatment and was accompanied by T-cell activation by blocking the PD-L1 immune checkpoint in both in vitro and in vivo models. Our current findings indicate that miR-424(322) regulates PD-L1 and CD80 expression. Therefore, miR-424(322) might serve as a therapeutic target to enhance the chemosensitivity of ovarian cancer cells through checkpoint blockage, which thereby promotes the T-cell response in attacking tumour cells.

Key Molecule: Programmed cell death 1 ligand 1 (PD-L1) [105]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PD-L1/PD-1 signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: T-cell apoptosis assay
• Mechanism Description: High expression levels of miR-424(322) were positively correlated with the PFS of ovarian cancer patients. miR-424(322) overexpression reduced PD-L1 and CD80 expression through direct binding to the 3'-UTR of these genes. Furthermore, low miR-424(322) and high PD-L1 expression were significantly correlated and strongly associated with chemoresistant phenotypes in ovarian cancer cells and tissues. Restoration of miR-424(322) expression (+) the sensitivity of cancer cells to drug treatment and was accompanied by T-cell activation by blocking the PD-L1 immune checkpoint in both in vitro and in vivo models. Our current findings indicate that miR-424(322) regulates PD-L1 and CD80 expression. Therefore, miR-424(322) might serve as a therapeutic target to enhance the chemosensitivity of ovarian cancer cells through checkpoint blockage, which thereby promotes the T-cell response in attacking tumour cells.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [106]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-509-3p can not only downregulate the expression of XIAP in ovarian cancer cells but also inhibit the proliferation of EOC cells and increase their sensitivity to cisplatin-induced apoptosis.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [107]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU assay
• Mechanism Description: miR-101 overexpression decreased the expression of EZH2, reduced proliferation and migration of ovarian cancer cells, and resensitized drug-resistant cancer cells to cisplatin-induced cytotoxicity.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [108]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell cycle arrest; Activation; hsa04110
• Cell Pathway Regulation: MAPK signaling pathway; Regulation; hsa04010
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: GAS5 might regulate PARP1 expression by recruiting the transcription factor E2F4 to its promoter, and then affect the MAPk pathway activity and enhance sensitivity to DDP of OC both in vitro and in vivo.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [109]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
• Mechanism Description: Down-regulation of miR429 contributes to the development of drug resistance in epithelial ovarian cancer by targeting ZEB1.

Tongue cancer [ICD-11: 2B62]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-483-5p [112]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Regulation; hsa04210
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: TUNEL assay; Flow cytometry assay
• Mechanism Description: FIS1 is able to regulate mitochondrial fission and cisplatin sensitivity. miR-483-5p is responsible for the downregulation of FIS1 and can suppress mitochondrial fission and apoptosis by targeting FIS1. Mitochondrial fission affects cisplatin sensitivity via the miR-483-5p-FIS1 axis in cancer cells.

Key Molecule: hsa-mir-23a [113]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk signaling pathway; Activation; hsa04010
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-23a in both SCC-4 and Tca8113 cells markedly increased Twist expression, c-Jun N-terminal kinase (JNk) activity and the half maximal inhibitory concentration (IC50) of cisplain, and decreased cisplatin-induced apoptosis, all of which was abolished by knockdown of Twist or selective JNk inhibitor SP600125. On the other hand, knockdown of miR-23a significantly decreased Twist expression, JNk activity and IC50 of cisplain, and increased cisplatin-induced apoptosis, all of which was completely reversed by overexpression of Twist. The present study for the first time demonstrates that miR-23a promotes cisplatin chemoresistance and protects cisplatin-induced apoptosis in TSCC cells through inducing Twist expression by a JNk-dependent mechanism.

Key Molecule: hsa-mir-21 [114]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Programmed cell death 4 (PDCD4) is a tumor suppressor gene and loss of PDCD4 expression was found in multiple human cancers. PDCD4 is an important functional target of miR-21 and related to tumor invasion and transformation. miR-21 could modulate chemosensitivity of TSCC cells to cisplatin by targeting PDCD4.

Key Molecule: hsa-mir-21 [50]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 was found decreased as with chemosensitivity for cisplatin in the Tca/cisplatin cells.

Key Molecule: hsa-mir-214 [50]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-214 can induce cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway.

Key Molecule: hsa-mir-23a [50]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Topoisomerase II is involved in DNA replication, transcription and chromosome segregation, and the beta form of DNA topoisomerase II beta (TOP2B) functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. miR-23a is an up-stream regulator of TOP2B to realize the chemoresistance of cisplatin.

Key Molecule: KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) [115]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue cancer [ICD-11: 2B62.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Ezrin/FAKT/Src signaling pathway; Activation; hsa05205
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Microarray; RT-PCR
• Experiment for Drug Resistance: MTS assay; EdU assay; Flow cytometric analysis
• Mechanism Description: KCNQ1OT1 promotes TSCC cell proliferation and chemo-resistance via the regulation of miR-211-5p mediated Ezrin/Fak/Src signaling.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Polycomb complex protein BMI-1 (BMI1) [28]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue cancer [ICD-11: 2B62.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Activation; hsa05217
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of BMI1 alters cell proliferation, apoptosis and stem cell self-renewal and correlates with the invasion and metastasis of several human cancers. BMI1 overexpression due to reduction of miR-200b and miR-15b may result in chemotherapy-induced EMT in TSCCs via these pathways.

Key Molecule: hsa-mir-15b [28]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Tongue cancer [ICD-11: 2B62.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Activation; hsa05217
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of BMI1 alters cell proliferation, apoptosis and stem cell self-renewal and correlates with the invasion and metastasis of several human cancers. BMI1 overexpression due to reduction of miR-200b and miR-15b may result in chemotherapy-induced EMT in TSCCs via these pathways.

Key Molecule: hsa-mir-200b [28]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Tongue cancer [ICD-11: 2B62.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Activation; hsa05217
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of BMI1 alters cell proliferation, apoptosis and stem cell self-renewal and correlates with the invasion and metastasis of several human cancers. BMI1 overexpression due to reduction of miR-200b and miR-15b may result in chemotherapy-induced EMT in TSCCs via these pathways.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [116]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Overexpression of CILA1 also increased the phosphorylation of GSk-3beta, resulting resistance in tongue cancar.

Key Molecule: Long non-protein coding RNA (CILA1) [116]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Overexpression of CILA1 also increased the phosphorylation of GSk-3beta, resulting resistance in tongue cancar.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mitochondrial fission 1 protein (FIS1) [112]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Regulation; hsa04210
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assay; Flow cytometry assay
• Mechanism Description: FIS1 is able to regulate mitochondrial fission and cisplatin sensitivity. miR-483-5p is responsible for the downregulation of FIS1 and can suppress mitochondrial fission and apoptosis by targeting FIS1. Mitochondrial fission affects cisplatin sensitivity via the miR-483-5p-FIS1 axis in cancer cells.

Key Molecule: Twist-related protein 1 (TWST1) [113]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk signaling pathway; Activation; hsa04010
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-23a in both SCC-4 and Tca8113 cells markedly increased Twist expression, c-Jun N-terminal kinase (JNk) activity and the half maximal inhibitory concentration (IC50) of cisplain, and decreased cisplatin-induced apoptosis, all of which was abolished by knockdown of Twist or selective JNk inhibitor SP600125. On the other hand, knockdown of miR-23a significantly decreased Twist expression, JNk activity and IC50 of cisplain, and increased cisplatin-induced apoptosis, all of which was completely reversed by overexpression of Twist. The present study for the first time demonstrates that miR-23a promotes cisplatin chemoresistance and protects cisplatin-induced apoptosis in TSCC cells through inducing Twist expression by a JNk-dependent mechanism.

Key Molecule: Programmed cell death protein 4 (PDCD4) [114]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Programmed cell death 4 (PDCD4) is a tumor suppressor gene and loss of PDCD4 expression was found in multiple human cancers. PDCD4 is an important functional target of miR-21 and related to tumor invasion and transformation. miR-21 could modulate chemosensitivity of TSCC cells to cisplatin by targeting PDCD4.

Key Molecule: DNA topoisomerase 2-beta (TOP2B) [50]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Topoisomerase II is involved in DNA replication, transcription and chromosome segregation, and the beta form of DNA topoisomerase II beta (TOP2B) functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. miR-23a is an up-stream regulator of TOP2B to realize the chemoresistance of cisplatin.

Key Molecule: Ezrin (EZR) [115]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Tongue cancer [ICD-11: 2B62.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Ezrin/FAKT/Src signaling pathway; Activation; hsa05205
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; EdU assay; Flow cytometric analysis
• Mechanism Description: KCNQ1OT1 promotes TSCC cell proliferation and chemo-resistance via the regulation of miR-211-5p mediated Ezrin/Fak/Src signaling.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-203 [117]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PIk3CA signaling pathway; Regulation; hsa04211
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-203 expression is much lower in the clinical tongue cancer samples. In the surviving Tca8113 cells after cisplatin treatment, miR-203 expression was much lower. Delivery of miR-203 sensitized the Tca8113 cells to cisplatin induced cell death through downregulation of PIk3CA.

Key Molecule: hsa-mir-21 [118]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CA-27 cells; Mouth; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of miR-21 could sensitize CA-27 cells to cisplatin possibly by increasing cisplatin induced apoptosis.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-181a [119]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: miR181a-Twist1 signaling pathway; Regulation; hsa05206
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin chemoresistance induced EMT, enhanced metastatic potential and down-regulated miR-181a in TSCC cells, miR-181a directly targeted Twist1 and then reversed chemoresistance and EMT in TSCC cells, miR-181a-Twist1 pathway may play an important role in the development of cisplatin-chemoresistance.

Key Molecule: hsa-miR-485-5p [120]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC25-res cells; Tongue; Homo sapiens (Human); CVCL_A5BQ
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: Hsa-miR485-5p reverses epithelial to mesenchymal transition and promotes cisplatin-induced cell death by targeting PAk1 in oral tongue squamous cell carcinom. Overexpression of p21 (RAC1) activated kinase 1 (PAk1) induced epithelial to mesenchymal transition (EMT) and significantly promoted the invasion and migration of oral squamous cell carcinoma SCC25 cells.

Key Molecule: Serine/threonine-protein kinase PAK 1 (PAK1) [120]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC25-res cells; Tongue; Homo sapiens (Human); CVCL_A5BQ
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: Hsa-miR485-5p reverses epithelial to mesenchymal transition and promotes cisplatin-induced cell death by targeting PAk1 in oral tongue squamous cell carcinom. Overexpression of p21 (RAC1) activated kinase 1 (PAk1) induced epithelial to mesenchymal transition (EMT) and significantly promoted the invasion and migration of oral squamous cell carcinoma SCC25 cells.

Key Molecule: hsa-mir-15b [121]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Oral tongue squamous cell cancer [ICD-11: 2B62.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC25-res cells; Tongue; Homo sapiens (Human); CVCL_A5BQ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: miR15b inhibits cancer-initiating cell phenotypes and chemoresistance of cisplatin by targeting TRIM14 in oral tongue squamous cell cancer Overexpression of TRIM14 induced EMT phenotype.

Key Molecule: Tripartite motif-containing protein 14 (TRIM14) [121]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral tongue squamous cell cancer [ICD-11: 2B62.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC25-res cells; Tongue; Homo sapiens (Human); CVCL_A5BQ
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: miR15b inhibits cancer-initiating cell phenotypes and chemoresistance of cisplatin by targeting TRIM14 in oral tongue squamous cell cancer Overexpression of TRIM14 induced EMT phenotype.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [117]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PIk3CA signaling pathway; Regulation; hsa04211
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-203 expression is much lower in the clinical tongue cancer samples. In the surviving Tca8113 cells after cisplatin treatment, miR-203 expression was much lower. Delivery of miR-203 sensitized the Tca8113 cells to cisplatin induced cell death through downregulation of PIk3CA.

Key Molecule: Twist-related protein 1 (TWST1) [119]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Tongue squamous cell carcinoma [ICD-11: 2B62.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: miR181a-Twist1 signaling pathway; Regulation; hsa05206
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin chemoresistance induced EMT, enhanced metastatic potential and down-regulated miR-181a in TSCC cells, miR-181a directly targeted Twist1 and then reversed chemoresistance and EMT in TSCC cells, miR-181a-Twist1 pathway may play an important role in the development of cisplatin-chemoresistance.

Nasopharyngeal cancer [ICD-11: 2B6B]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125a [19]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: CNE-2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6888
• In Vitro Model: TW03 cells; Nasopharynx; Homo sapiens (Human); CVCL_6010
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In the TW03/DDP cells, the expression levels of miR 125a and miR 125b were upregulated, and this caused downregulation of p53. Ectopic expression of these miRNAs in the TW03 cell model sensitized TW03 to cisplatin by decreasing the protein expression levels of p53, whereas ectopic expression in the antisense oligos of these microRNAs demonstrated the opposite effect. In addition, the present demonstrated that the cisplatin induced expression of miR 125a and miR 125b inhibited cisplatin induced apoptosis in the TW03 cells by decreasing the protein expression levels of p53. Taken together, the present study revealed for the first time, to the best of our knowledge, that induction of the expression of miR 125a and miR 125b by treatment with cisplatin resulted in resistance to the cisplatin drug in the NPC cells.

Key Molecule: hsa-mir-125b [19]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: CNE-2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6888
• In Vitro Model: TW03 cells; Nasopharynx; Homo sapiens (Human); CVCL_6010
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In the TW03/DDP cells, the expression levels of miR 125a and miR 125b were upregulated, and this caused downregulation of p53. Ectopic expression of these miRNAs in the TW03 cell model sensitized TW03 to cisplatin by decreasing the protein expression levels of p53, whereas ectopic expression in the antisense oligos of these microRNAs demonstrated the opposite effect. In addition, the present demonstrated that the cisplatin induced expression of miR 125a and miR 125b inhibited cisplatin induced apoptosis in the TW03 cells by decreasing the protein expression levels of p53. Taken together, the present study revealed for the first time, to the best of our knowledge, that induction of the expression of miR 125a and miR 125b by treatment with cisplatin resulted in resistance to the cisplatin drug in the NPC cells.

Key Molecule: X inactive specific transcript (XIST) [122]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA XIST modulates cisplatin resistance by altering PDCD4 and Fas-Lexpressions in human nasopharyngeal carcinoma HNE1 cells in vitro. XIST is up-regulated in HNE1/DDP cells, and down-regulation and up-regulation of XIST expression reduce and increase DDP resistance of the cells, respectively, possibly as a result of changes in the expressions of PDCD4 and Fas-L.

Key Molecule: CDKN2B antisense RNA 1 (CDKN2B-AS1) [41]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Tumorigenic properties; Inhibition; hsa05200
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: NP69 cells; Nasopharynx; Homo sapiens (Human); CVCL_F755
• In Vitro Model: S18 cells; Nasopharynx; Homo sapiens (Human); CVCL_B0U9
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC apoptosis assay
• Mechanism Description: ANRIL directly interacts with let-7a and regulates its expression, ANRIL could directly bind to let-7a and negatively regulate let-7a expression. Down-regulation of LncRNA ANRIL represses tumorigenicity and enhances cisplatin-induced cytotoxicity via regulating microRNA let-7a in nasopharyngeal carcinoma.

Key Molecule: hsa-let-7a [41]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cytotoxicity; Inhibition; hsa04650
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: NP69 cells; Nasopharynx; Homo sapiens (Human); CVCL_F755
• In Vitro Model: S18 cells; Nasopharynx; Homo sapiens (Human); CVCL_B0U9
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; RT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC apoptosis assay
• Mechanism Description: ANRIL directly interacts with let-7a and regulates its expression, ANRIL could directly bind to let-7a and negatively regulate let-7a expression. Down-regulation of LncRNA ANRIL represses tumorigenicity and enhances cisplatin-induced cytotoxicity via regulating microRNA let-7a in nasopharyngeal carcinoma.

Key Molecule: Testis associated oncogenic LncRNA (THORLNC) [123]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: HN12 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5518
• In Vitro Model: HN13 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5519
• In Vitro Model: HN30 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5525
• In Vitro Model: HN4 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_IS30
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell assay
• Mechanism Description: LncRNA THOR acts as a co-activator of YAP and promotes YAP transcriptional activity,facilitating NPC stemness and attenuate cisplatin sensitivity.

Key Molecule: Testis associated oncogenic LncRNA (THORLNC) [123]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: HN12 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5518
• In Vitro Model: HN13 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5519
• In Vitro Model: HN30 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5525
• In Vitro Model: HN4 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_IS30
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell assay
• Mechanism Description: LncRNA THOR acts as a co-activator of YAP and promotes YAP transcriptional activity,facilitating NPC stemness and attenuate cisplatin sensitivity.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [19]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: CNE-2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6888
• In Vitro Model: TW03 cells; Nasopharynx; Homo sapiens (Human); CVCL_6010
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In the TW03/DDP cells, the expression levels of miR 125a and miR 125b were upregulated, and this caused downregulation of p53. Ectopic expression of these miRNAs in the TW03 cell model sensitized TW03 to cisplatin by decreasing the protein expression levels of p53, whereas ectopic expression in the antisense oligos of these microRNAs demonstrated the opposite effect. In addition, the present demonstrated that the cisplatin induced expression of miR 125a and miR 125b inhibited cisplatin induced apoptosis in the TW03 cells by decreasing the protein expression levels of p53. Taken together, the present study revealed for the first time, to the best of our knowledge, that induction of the expression of miR 125a and miR 125b by treatment with cisplatin resulted in resistance to the cisplatin drug in the NPC cells.

Key Molecule: Tumor necrosis factor ligand superfamily member 6 (FASLG) [122]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA XIST modulates cisplatin resistance by altering PDCD4 and Fas-Lexpressions in human nasopharyngeal carcinoma HNE1 cells in vitro. XIST is up-regulated in HNE1/DDP cells, and down-regulation and up-regulation of XIST expression reduce and increase DDP resistance of the cells, respectively, possibly as a result of changes in the expressions of PDCD4 and Fas-L.

Key Molecule: Programmed cell death protein 4 (PDCD4) [122]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA XIST modulates cisplatin resistance by altering PDCD4 and Fas-Lexpressions in human nasopharyngeal carcinoma HNE1 cells in vitro. XIST is up-regulated in HNE1/DDP cells, and down-regulation and up-regulation of XIST expression reduce and increase DDP resistance of the cells, respectively, possibly as a result of changes in the expressions of PDCD4 and Fas-L.

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [123]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: HN12 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5518
• In Vitro Model: HN13 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5519
• In Vitro Model: HN30 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5525
• In Vitro Model: HN4 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_IS30
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Transwell assay
• Mechanism Description: LncRNA THOR acts as a co-activator of YAP and promotes YAP transcriptional activity,facilitating NPC stemness and attenuate cisplatin sensitivity.

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [123]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• In Vitro Model: HN12 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5518
• In Vitro Model: HN13 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5519
• In Vitro Model: HN30 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5525
• In Vitro Model: HN4 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_IS30
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell assay
• Mechanism Description: LncRNA THOR acts as a co-activator of YAP and promotes YAP transcriptional activity,facilitating NPC stemness and attenuate cisplatin sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-203 [124]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: There is a directly negative feedback loop between miR203 and ZEB2 participating in tumor stemness and chemotherapy resistance.

Key Molecule: hsa-mir-29c [125]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vitro Model: HNE-2 cells; Nasopharynx; Homo sapiens (Human); CVCL_FA07
• In Vivo Model: SCID-Beige nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-29c repressed expression of anti-apoptotic factors, Mcl-1 and Bcl-2 in NPC tissues and cell lines, cause the resstance to Cisplatin.

Key Molecule: hsa-mir-183 [126]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR183 overexpression inhibits tumorigenesis and enhances DDP-induced cytotoxicity by targeting MTA1 in nasopharyngeal carcinoma.

Key Molecule: hsa-mir-125b [127]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: CNE2/DDP cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay-directed annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) assay
• Mechanism Description: microRNA-125b reverses the multidrug resistance of nasopharyngeal carcinoma cells via targeting of Bcl-2.

Key Molecule: hsa-miR-19b-1-5p [128]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: NP69 cells; Nasopharynx; Homo sapiens (Human); CVCL_F755
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vitro Model: C666 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_M597
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: microRNA-19b Promotes Nasopharyngeal Carcinoma More Sensitive to Cisplatin by Suppressing kRAS.

Key Molecule: hsa-let-7a-5p [129]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Regulation; hsa05200
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Inhibition; hsa04010
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: S18 cells; Nasopharynx; Homo sapiens (Human); CVCL_B0U9
• In Vitro Model: Hk-1 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_7047
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; EdU assay
• Mechanism Description: Upregulation of let-7a-5p reduced cell viability in S18 and 5-8F cells in the presence of 10 ug/ml cisplatin, which was reversed by upregulation of NEAT1;NEAT1 downregulates the expression of Rsf-1 through let-7a-5p.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [129]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Inhibition; hsa04010
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: S18 cells; Nasopharynx; Homo sapiens (Human); CVCL_B0U9
• In Vitro Model: Hk-1 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_7047
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; EdU assay
• Mechanism Description: Upregulation of let-7a-5p reduced cell viability in S18 and 5-8F cells in the presence of 10 ug/ml cisplatin, which was reversed by upregulation of NEAT1;NEAT1 downregulates the expression of Rsf-1 through let-7a-5p.

Key Molecule: hsa-mir-132 [130]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-132 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while FOXA1 protein levels were decreased.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [131]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vivo Model: BALB/c nude mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Lentiviral vectors were constructed to allow an efficient expression of anti-ABCC2 siRNA. The accumulation of intracellular cisplatin in these CNE2 cell clones with reduced expression of ABCC2 increased markedly, accompanied by increased sensitivity against cisplatin. lentivirus-mediated RNAi silencing targeting ABCC2 might reverse the ABCC2-related drug resistance of NPC cell line CNE2 against cisplatin.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [132]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The upregulation of miR-139-5p significantly increases DDP-induced apoptosis in NPC cells and modulates ZEB1 expression.

Key Molecule: hsa-miR-139-5p [132]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The upregulation of miR-139-5p significantly increases DDP-induced apoptosis in NPC cells and modulates ZEB1 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2) [124]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: There is a directly negative feedback loop between miR203 and ZEB2 participating in tumor stemness and chemotherapy resistance.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [125]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vitro Model: HNE-2 cells; Nasopharynx; Homo sapiens (Human); CVCL_FA07
• In Vivo Model: SCID-Beige nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-29c repressed expression of anti-apoptotic factors, Mcl-1 and Bcl-2 in NPC tissues and cell lines, cause the resstance to Cisplatin.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [125]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vitro Model: HNE-2 cells; Nasopharynx; Homo sapiens (Human); CVCL_FA07
• In Vivo Model: SCID-Beige nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-29c repressed expression of anti-apoptotic factors, Mcl-1 and Bcl-2 in NPC tissues and cell lines, cause the resstance to Cisplatin.

Key Molecule: Metastasis-associated protein MTA1 (MTA1) [126]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell cytotoxicity; Activation; hsa04650
• Cell Pathway Regulation: Tumorigenesis; Inhibition; hsa05200
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR183 overexpression inhibits tumorigenesis and enhances DDP-induced cytotoxicity by targeting MTA1 in nasopharyngeal carcinoma.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [127]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: CNE2/DDP cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay-directed annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) assay
• Mechanism Description: microRNA-125b reverses the multidrug resistance of nasopharyngeal carcinoma cells via targeting of Bcl-2.

Key Molecule: GTPase KRas (KRAS) [128]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: NP69 cells; Nasopharynx; Homo sapiens (Human); CVCL_F755
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• In Vitro Model: C666 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_M597
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: microRNA-19b Promotes Nasopharyngeal Carcinoma More Sensitive to Cisplatin by Suppressing kRAS.

Key Molecule: Remodeling and spacing factor 1 (RSF1) [129]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Inhibition; hsa04010
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: S18 cells; Nasopharynx; Homo sapiens (Human); CVCL_B0U9
• In Vitro Model: Hk-1 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_7047
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; EdU assay
• Mechanism Description: Upregulation of let-7a-5p reduced cell viability in S18 and 5-8F cells in the presence of 10 ug/ml cisplatin, which was reversed by upregulation of NEAT1;NEAT1 downregulates the expression of Rsf-1 through let-7a-5p.

Key Molecule: Hepatocyte nuclear factor 3-alpha (FOXA1) [130]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-132 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while FOXA1 protein levels were decreased.

Oral squamous cell carcinoma [ICD-11: 2B6E]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-29a [21]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-29a expression was decreased in clinical OSCC cancer specimens. miR-29a negatively regulated MMP2 transcription and translation through directly binding to 3'-UTR. miR-29a overexpression could inhibit OSCC cancer cell invasion and anti-apoptotic ability, and vice versa.

Key Molecule: hsa-miR-654-5p [133]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR654-5p targets GRAP to promote proliferation, metastasis, and chemoresistance of oral squamous cell carcinoma through Ras/MAPk signaling.

Key Molecule: CDKN2B antisense RNA 1 (CDKN2B-AS1) [134]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: HSC3 cells; Tongue; Homo sapiens (Human); CVCL_1288
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: OSCC3 cells; Tongue; Homo sapiens (Human); CVCL_L894
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Midkine derived from cancer-associated fibroblasts promotes cisplatin-resistance via up-regulation of the expression of LncRNA ANRIL in tumour cells. ANRIL knockdown overcomes Mk-induced cisplatin resistance via activation of caspase-3-dependent apoptosis. Overexpression of LncRNA ANRIL promots the up-regulation of ABC family proteins MRP1 and ABCC2, which ultimately results in tumour cell resistance to cisplatin.

Key Molecule: hsa-miR-184 [135]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: NHOk cells; Tongue; Homo sapiens (Human); N.A.
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: TSCCA cells; Tongue; Homo sapiens (Human); CVCL_VL15
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Caspase-3 activity analysis
• Mechanism Description: LncRNA UCA1 promotes proliferation and cisplatin resistance of oral squamous cell carcinoma by sunppressing miR-184 expression.

Key Molecule: Urothelial cancer associated 1 (UCA1) [135]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: NHOk cells; Tongue; Homo sapiens (Human); N.A.
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: TSCCA cells; Tongue; Homo sapiens (Human); CVCL_VL15
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Caspase-3 activity analysis
• Mechanism Description: LncRNA UCA1 promotes proliferation and cisplatin resistance of oral squamous cell carcinoma by sunppressing miR-184 expression.

Key Molecule: hsa-mir-218 [136]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral cancer [ICD-11: 2B6E.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PPP2R5A/Wnt signaling pathway; Regulation; hsa04310
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: MDA-1386Ln cells; Tongue; Homo sapiens (Human); CVCL_H541
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• In Vitro Model: UM1 cells; Tongue; Homo sapiens (Human); CVCL_VH00
• In Vitro Model: UM2 cells; Tongue; Homo sapiens (Human); CVCL_VH01
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-218 promotes cisplatin resistance in oral cancer via the PPP2R5A/Wnt signaling pathway. Suppression of miR218 or PPP2R5A significantly promoted or reduced cisplatin-induced apoptosis, respectively. PPP2R5A overexpression or beta-catenin knockdown inhibited miR218-mediated Wnt activation and partially restored cell sensitivity.

Key Molecule: Long noncoding RNA lnc-IL7R (Lnc-IL7R) [42]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: HSC3 cells; Tongue; Homo sapiens (Human); CVCL_1288
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: OSCC3 cells; Tongue; Homo sapiens (Human); CVCL_L894
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: HIOEC-B cells; Tongue; Homo sapiens (Human); CVCL_6E44
• In Vitro Model: SCC-14a cells; Tongue; Homo sapiens (Human); CVCL_7719
• In Vitro Model: SCC-14b cells; Tongue; Homo sapiens (Human); CVCL_7720
• In Vitro Model: SCC1 cells; Tongue; Homo sapiens (Human); CVCL_A5SA
• Experiment for Molecule Alteration: Q-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, knockdown of lnc-IL7R improved the chemotherapy sensitivity.

Key Molecule: Toll-like receptor 3 (TLR3) [42]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: HSC3 cells; Tongue; Homo sapiens (Human); CVCL_1288
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: OSCC3 cells; Tongue; Homo sapiens (Human); CVCL_L894
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: HIOEC-B cells; Tongue; Homo sapiens (Human); CVCL_6E44
• In Vitro Model: SCC-14a cells; Tongue; Homo sapiens (Human); CVCL_7719
• In Vitro Model: SCC-14b cells; Tongue; Homo sapiens (Human); CVCL_7720
• In Vitro Model: SCC1 cells; Tongue; Homo sapiens (Human); CVCL_A5SA
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, knockdown of lnc-IL7R improved the chemotherapy sensitivity.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [134]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: HSC3 cells; Tongue; Homo sapiens (Human); CVCL_1288
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: OSCC3 cells; Tongue; Homo sapiens (Human); CVCL_L894
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Midkine derived from cancer-associated fibroblasts promotes cisplatin-resistance via up-regulation of the expression of LncRNA ANRIL in tumour cells. ANRIL knockdown overcomes Mk-induced cisplatin resistance via activation of caspase-3-dependent apoptosis. Overexpression of LncRNA ANRIL promots the up-regulation of ABC family proteins MRP1 and ABCC2, which ultimately results in tumour cell resistance to cisplatin.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [134]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: HSC3 cells; Tongue; Homo sapiens (Human); CVCL_1288
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• In Vitro Model: OSCC3 cells; Tongue; Homo sapiens (Human); CVCL_L894
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Midkine derived from cancer-associated fibroblasts promotes cisplatin-resistance via up-regulation of the expression of LncRNA ANRIL in tumour cells. ANRIL knockdown overcomes Mk-induced cisplatin resistance via activation of caspase-3-dependent apoptosis. Overexpression of LncRNA ANRIL promots the up-regulation of ABC family proteins MRP1 and ABCC2, which ultimately results in tumour cell resistance to cisplatin.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [137]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral cancer [ICD-11: 2B6E.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UM-SCC-1 cells; Ovary; Homo sapiens (Human); CVCL_7707
• In Vitro Model: WSU-HN30 cells; Pleural effusion; Homo sapiens (Human); CVCL_5525
• In Vitro Model: WSU-HN6 cells; Urinary bladder; Homo sapiens (Human); CVCL_5516
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: E-cigarette aerosol exposure alters the expression of drug influx and efflux transporters.Among the other drug efflux ATPase genes previously reported to contribute to cisplatin resistance ABCG2, ABCC2, ABCA1, and ABCC1 were significantly up-regulated in at least one cell line.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Collagenase 72 kDa type IV collagenase (MMP2) [21]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-29a expression was decreased in clinical OSCC cancer specimens. miR-29a negatively regulated MMP2 transcription and translation through directly binding to 3'-UTR. miR-29a overexpression could inhibit OSCC cancer cell invasion and anti-apoptotic ability, and vice versa.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GRB2-related adapter protein (GRAP) [133]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR654-5p targets GRAP to promote proliferation, metastasis, and chemoresistance of oral squamous cell carcinoma through Ras/MAPk signaling.

Key Molecule: Steroidogenic factor 1 (STF1) [135]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell adhesion; Activation; hsa04514
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: NHOk cells; Tongue; Homo sapiens (Human); N.A.
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: TSCCA cells; Tongue; Homo sapiens (Human); CVCL_VL15
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Caspase-3 activity analysis
• Mechanism Description: UCA1 accelerated proliferation, increased CDDP chemoresistance and restrained apoptosis partly through modulating SF1 via sponging miR-184 in OSCC cells. UCA1 promoted the expression of SF1 by sponging miR-184 in CDDP-resistant OSCC cells.

Key Molecule: PP2A B subunit isoform R5-alpha (PPP2R5A) [136]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oral cancer [ICD-11: 2B6E.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PPP2R5A/Wnt signaling pathway; Regulation; hsa04310
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: MDA-1386Ln cells; Tongue; Homo sapiens (Human); CVCL_H541
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• In Vitro Model: UM1 cells; Tongue; Homo sapiens (Human); CVCL_VH00
• In Vitro Model: UM2 cells; Tongue; Homo sapiens (Human); CVCL_VH01
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-218 promotes cisplatin resistance in oral cancer via the PPP2R5A/Wnt signaling pathway. Suppression of miR218 or PPP2R5A significantly promoted or reduced cisplatin-induced apoptosis, respectively. PPP2R5A overexpression or beta-catenin knockdown inhibited miR218-mediated Wnt activation and partially restored cell sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-222 [138]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: UM1 cells; Tongue; Homo sapiens (Human); CVCL_VH00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Antisense (As)-miR-222 inhibits the expression of miR-222. In contrast, PUMA was dramaticallyup-regulated. IC50 values were significantly decreased in cells treated with As-miR-222 combined with CDDP, to a greater extent than in cells treated with CDDP alone. Furthermore, As-miR-222 (+) apoptosis and inhibited the invasiveness of UM1 cells. Analysis of the above data suggested that, in UM1 cells, there might be a regulatory loop between miR-222 and PUMA, and that miR-222 inhibition increased the chemosensitivity to CDDP.

Key Molecule: hsa-mir-27b [139]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: FZD7/beta-catenin signaling pathway; Activation; hsa05224
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Colony formation assay; Flow cytometry assay
• Mechanism Description: miR-27b can increase the sensitivity of OSCC cells to cisplatin drugs, significantly inhibit OSCC cell proliferation, promote cell apoptosis, and inhibit cell invasion and migration, which may be related to the inhibition of FDZ7/beta-catenin signaling pathway by miR-27b.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [140]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule-associated protein 1 light chain 3B), beclin1, and autophagy-related gene (ATG) 3 and ATG7. The expressions of mTOR increased, which promoted the sensitivity to cisplatin.

Key Molecule: hsa-let-7c [141]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Oral cancer [ICD-11: 2B6E.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: GNM cells; Oral; Homo sapiens (Human); CVCL_WL58
• In Vitro Model: SAS cells; Oral; Homo sapiens (Human); CVCL_1675
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The inhibitory effect of let-7c on various stemness phenotypes was reverted by IL-8, indicating that lower expression of let-7c may confer higher cancer stemness through a failure to downregulate IL-8.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Cadherin-1 (CDH1) [142]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HULC-depleted cells showed decreased expression of vimentin and N-cadherin and increased expression of E-cadherin, which shows that HULC participates in the EMT process and affects the expression levels of proteins that are crucial for cell proliferation and invasion.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [142]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HULC-depleted cells showed decreased expression of vimentin and N-cadherin and increased expression of E-cadherin, which shows that HULC participates in the EMT process and affects the expression levels of proteins that are crucial for cell proliferation and invasion.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-binding component 3 (BBC3) [138]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: UM1 cells; Tongue; Homo sapiens (Human); CVCL_VH00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Antisense (As)-miR-222 inhibits the expression of miR-222. In contrast, PUMA was dramaticallyup-regulated. IC50 values were significantly decreased in cells treated with As-miR-222 combined with CDDP, to a greater extent than in cells treated with CDDP alone. Furthermore, As-miR-222 (+) apoptosis and inhibited the invasiveness of UM1 cells. Analysis of the above data suggested that, in UM1 cells, there might be a regulatory loop between miR-222 and PUMA, and that miR-222 inhibition increased the chemosensitivity to CDDP.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [140]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule-associated protein 1 light chain 3B), beclin1, and autophagy-related gene (ATG) 3 and ATG7. The expressions of mTOR increased, which promoted the sensitivity to cisplatin.

Key Molecule: Ubiquitin-like-conjugating enzyme ATG3 (ATG3) [140]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule-associated protein 1 light chain 3B), beclin1, and autophagy-related gene (ATG) 3 and ATG7. The expressions of mTOR increased, which promoted the sensitivity to cisplatin.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [140]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule-associated protein 1 light chain 3B), beclin1, and autophagy-related gene (ATG) 3 and ATG7. The expressions of mTOR increased, which promoted the sensitivity to cisplatin.

Key Molecule: Beclin-1 (BECN1) [140]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule-associated protein 1 light chain 3B), beclin1, and autophagy-related gene (ATG) 3 and ATG7. The expressions of mTOR increased, which promoted the sensitivity to cisplatin.

Key Molecule: Autophagy-related protein LC3 B (MAP1LC3B) [140]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: KB cells; Gastric; Homo sapiens (Human); CVCL_0372
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: After HOTAIR silence, autophagy was inhibited with the downregulated expression of MAP1LC3B (microtubule-associated protein 1 light chain 3B), beclin1, and autophagy-related gene (ATG) 3 and ATG7. The expressions of mTOR increased, which promoted the sensitivity to cisplatin.

Key Molecule: Interleukin-8 (IL8) [141]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral cancer [ICD-11: 2B6E.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: GNM cells; Oral; Homo sapiens (Human); CVCL_WL58
• In Vitro Model: SAS cells; Oral; Homo sapiens (Human); CVCL_1675
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The inhibitory effect of let-7c on various stemness phenotypes was reverted by IL-8, indicating that lower expression of let-7c may confer higher cancer stemness through a failure to downregulate IL-8.

Esophageal cancer [ICD-11: 2B70]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200c [143]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Activation; hsa04520
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: 2774 cells; Ovary; Homo sapiens (Human); CVCL_0420
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: KLE cells; Ovary; Homo sapiens (Human); CVCL_1329
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: BRD7 is known to mediate tumor suppression by down-regulation of the beta-catenin pathway through accumulation of beta-catenin in the cytoplasm. miR-200c regulated the translocation of beta-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc, miR-200c induces additive effect on the cisplatin cytotoxicity of endometrial carcinoma cells.

Key Molecule: hsa-mir-141 [35]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: KYSE170 cells; Esophagus; Homo sapiens (Human); CVCL_1358
• In Vitro Model: KYSE190 cells; Esophagus; Homo sapiens (Human); CVCL_8301
• In Vitro Model: KYSE520 cells; Esophagus; Homo sapiens (Human); CVCL_1355
• In Vitro Model: KYSE590 cells; Esophagus; Homo sapiens (Human); CVCL_8508
• In Vitro Model: KYSE890 cells; Esophagus; Homo sapiens (Human); CVCL_A103
• In Vitro Model: KYSE960 cells; Esophagus; Homo sapiens (Human); CVCL_8512
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: When miR-141, which was the most highly expressed miRNA in the cisplatin-resistant cell lines, was expressed ectopically in thecisplatin-sensitive cell lines, cell viability after cisplatin treatment was increased significantly. miR-141 directly targeted the 3 -untranslated region ofYAP1, which is known to have a crucial role in apoptosis inducedby DNA-damaging agents, and thus downregulated YAP1 expression.

Key Molecule: hsa-mir-200c [8]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-200c as the miRNA responsible for chemoresistance in esophageal cancer. knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A (PP2A), which is known to inhibit the phosphorylation of Akt, miR-200c-induced resistance is mediated through the Akt pathway.

Key Molecule: Taurine up-regulated 1 (TUG1) [144]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted cell resistance to DDP, at least in part, through upregulating Nrf2.

Key Molecule: hsa-miR-455-3p [145]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/beta-catenin/TGF-beta signaling pathway; Activation; hsa04310
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Tumor volume measurement; Luciferase assay
• Mechanism Description: Antagonizing miR455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. Treatment with a miR455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [144]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted DDP resistance in TE-1 and TE-1/DDP cells by promoting cell proliferation, suppressing cell apoptosis, and elevating protein expression of the classical multi-drug resistance-related P-gp.

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [146]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of ATP7A in EC109/cisplatin cells might increase pumping platinum out of cells or binding and sequestration of platinum drugs, then decrease cellular platinum concentration or keep them away from accessing their key cytotoxic targets in the nucleus, finally result in cisplatin-resistance.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-27a [147]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27 in serum originated mainly from esophageal cancer cells, because its serum expression level in patients with esophageal cancer was significantly higher than that of healthy volunteers and decreased significantly after surgery compared with the baseline (before surgery). Moreover, co-culture of fibroblasts with anti-miR-27-transfected esophageal cancer cells resulted in a major decrease in the antiapoptotic function of fibroblasts, compared with fibroblasts co-cultured with control esophageal cancer cells that secrete extracellular miR-27. Serum miR-27 level may reflect the expression level of extracellular miR-27 derived from esophageal cancer cells. miR-27 is involved in resistance to chemotherapy in esophageal cancer, through miR-27 -induced transformation of NOF into CAF, and that TGF-beta secreted from these CAF-like fibroblasts induces chemoresistance to cisplatin in esophageal cancer.

Key Molecule: hsa-mir-27b [147]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27 in serum originated mainly from esophageal cancer cells, because its serum expression level in patients with esophageal cancer was significantly higher than that of healthy volunteers and decreased significantly after surgery compared with the baseline (before surgery). Moreover, co-culture of fibroblasts with anti-miR-27-transfected esophageal cancer cells resulted in a major decrease in the antiapoptotic function of fibroblasts, compared with fibroblasts co-cultured with control esophageal cancer cells that secrete extracellular miR-27. Serum miR-27 level may reflect the expression level of extracellular miR-27 derived from esophageal cancer cells. miR-27 is involved in resistance to chemotherapy in esophageal cancer, through miR-27 -induced transformation of NOF into CAF, and that TGF-beta secreted from these CAF-like fibroblasts induces chemoresistance to cisplatin in esophageal cancer.

Key Molecule: TGF-beta receptor type I (TGFBR1) [147]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: Elisa assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27 in serum originated mainly from esophageal cancer cells, because its serum expression level in patients with esophageal cancer was significantly higher than that of healthy volunteers and decreased significantly after surgery compared with the baseline (before surgery). Moreover, co-culture of fibroblasts with anti-miR-27-transfected esophageal cancer cells resulted in a major decrease in the antiapoptotic function of fibroblasts, compared with fibroblasts co-cultured with control esophageal cancer cells that secrete extracellular miR-27. Serum miR-27 level may reflect the expression level of extracellular miR-27 derived from esophageal cancer cells. miR-27 is involved in resistance to chemotherapy in esophageal cancer, through miR-27 -induced transformation of NOF into CAF, and that TGF-beta secreted from these CAF-like fibroblasts induces chemoresistance to cisplatin in esophageal cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bromodomain-containing protein 7 (BRD7) [143]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Activation; hsa04520
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: 2774 cells; Ovary; Homo sapiens (Human); CVCL_0420
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: KLE cells; Ovary; Homo sapiens (Human); CVCL_1329
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: BRD7 is known to mediate tumor suppression by down-regulation of the beta-catenin pathway through accumulation of beta-catenin in the cytoplasm. miR-200c regulated the translocation of beta-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc, miR-200c induces additive effect on the cisplatin cytotoxicity of endometrial carcinoma cells.

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [35]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: KYSE170 cells; Esophagus; Homo sapiens (Human); CVCL_1358
• In Vitro Model: KYSE190 cells; Esophagus; Homo sapiens (Human); CVCL_8301
• In Vitro Model: KYSE520 cells; Esophagus; Homo sapiens (Human); CVCL_1355
• In Vitro Model: KYSE590 cells; Esophagus; Homo sapiens (Human); CVCL_8508
• In Vitro Model: KYSE890 cells; Esophagus; Homo sapiens (Human); CVCL_A103
• In Vitro Model: KYSE960 cells; Esophagus; Homo sapiens (Human); CVCL_8512
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: When miR-141, which was the most highly expressed miRNA in the cisplatin-resistant cell lines, was expressed ectopically in thecisplatin-sensitive cell lines, cell viability after cisplatin treatment was increased significantly. miR-141 directly targeted the 3 -untranslated region ofYAP1, which is known to have a crucial role in apoptosis inducedby DNA-damaging agents, and thus downregulated YAP1 expression.

Key Molecule: PP2A subunit A isoform R1-beta (PPP2R1B) [8]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-200c as the miRNA responsible for chemoresistance in esophageal cancer. knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A (PP2A), which is known to inhibit the phosphorylation of Akt, miR-200c-induced resistance is mediated through the Akt pathway.

Key Molecule: NFE2-related factor 2 (NRF2) [144]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: RNA pull-down assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted cell resistance to DDP, at least in part, through upregulating Nrf2.

Key Molecule: Transcription factor SOX-9 (SOX9) [148]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell motility; Activation; hsa04510
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Self-renewal signaling pathway; Activation; hsa04550
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• Experiment for Molecule Alteration: Dual luciferase reporter assay; RNA-binding protein immunoprecipitation; Western blot analysis
• Experiment for Drug Resistance: CCK8, colony formation, Transwell, and sphere-forming assay
• Mechanism Description: Linc-ROR modulating the derepression of SOX9 by directly sponging multiple miRNAs including miR15b, miR33a, miR129, miR145, and miR206. Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [20]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [20]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-187 [149]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PTEN and TNF were demonstrated to be upregulated following miR-187 overexpression. TNF is a cytokine that regulates multiple cellular processes including proliferation and apoptosis. PTEN acts as a tumor suppressor and regulates the PI3k/AkT pathway, which has been identified as a radiation response pathway. The upregulation of PTEN enhances radiosensitivity via the downregulation of the PI3k/AkT pathway.

Key Molecule: hsa-let-7g [150]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal carcinoma [ICD-11: 2B70.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs.

Key Molecule: hsa-let-7i [150]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal carcinoma [ICD-11: 2B70.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs.

Key Molecule: hsa-mir-96 [151]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; CCK8 assay
• Mechanism Description: Ectopic overexpression of miR-96 in TE-1 or ECa-109 contributed to tumor growth in xenograft mouse models. Furthermore, up-regulation of miR-96 could reduce the susceptibilities of EC cells to chemotherapy or radiotherapy. RECk was identified as a target of miR-96 and RECk overexpressing could abrogate the growth of EC cells induced by miR-96. Taken together, miR-96 serves as an oncogene role in EC cells through downregulating RECk.

Key Molecule: hsa-mir-200c [152]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Endoscopy; Computed tomography assay; Positron emission tomography assay
• Mechanism Description: Serum miR-200c levels are useful for predicting the response to chemotherapy (cisplatin, 5-fluorouracil, and Adriamycin (ACF) or cisplatin, 5-fluorouracil, and docetaxel (DCF) ) in patients with esophageal cancer who underwent preoperative chemotherapy followed by surgery.

Key Molecule: hsa-mir-223 [153]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Key Molecule: hsa-let-7c [154]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: IL6/STAT3 signaling signaling pathway; Inhibition; hsa04659
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vitro Model: TE1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: TE11 cells; Esophagus; Homo sapiens (Human); CVCL_1761
• In Vitro Model: TE5 cells; Esophagus; Homo sapiens (Human); CVCL_1764
• In Vitro Model: TE9 cells; Esophagus; Homo sapiens (Human); CVCL_1767
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Let-7c directly repressed cisplatin-activated interleukin (IL) -6/STAT3 prosurvival pathway, restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin.

Key Molecule: hsa-mir-148a [155]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-148a sensitized chemotherapy-sensitive oesophageal cancer cell lines to cisplatin and, to a lesser extent, to 5-flurouracil and attenuated resistance in chemotherapy-resistant variants.

Key Molecule: hsa-mir-148a [155]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-148a sensitized chemotherapy-sensitive oesophageal cancer cell lines to cisplatin and, to a lesser extent, to 5-flurouracil and attenuated resistance in chemotherapy-resistant variants.

Key Molecule: hsa-mir-296 [156]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Down-regulation of miR-296 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs on esophageal cancer cells, and might promote ADR-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of ADR. Down-regulation of miR-296 could significantly decrease the expression of P-glycoprotein, Bcl-2, and the transcription of MDR1, but up-regulate the expression of Bax.

Key Molecule: hsa-mir-27a [157]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of miR-27a significantly decreased expression of MDR1, but did not alter the expression of MRP, miR-27a could possibly mediate drug resistance, at least in part through regulation of MDR1 and apoptosis.

Key Molecule: hsa-miR-130a-3p [158]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-130a-3p downregulation on enhancement of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the increase of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: hsa-miR-130a-3p [158]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-130a-3p upregulation on suppression of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the inhibition of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: hsa-miR-148a-3p [158]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-148a-3p downregulation on enhancement of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the increase of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: hsa-miR-148a-3p [158]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-148a-3p upregulation on suppression of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the inhibition of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: Prostate cancer associated transcript 1 (PCAT1) [159]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of PCAT-1 increased the proliferation rate and growth of OC cells. Inhibition of PCAT-1 decreased proliferation and growth of OC cells, and increased cisplatin chemosensitivity. PCAT-1 promotes development of OC and represses the chemoresistance of OC to cisplatin.

Key Molecule: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8) [148]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; hsa04662
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8, colony formation, Transwell, and sphere-forming assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: hsa-miR-125a-5p [160]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Inhibition; hsa04550
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: EC1 cells; Esophagus; Homo sapiens (Human); CVCL_DC74
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Would healing assay; Invasion assay
• Mechanism Description: miR 125a 5p and cisplatin markedly inactivated the STAT3 signaling pathway.

Key Molecule: hsa-mir-224 [161]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: DESC1/EGFR/AKT signaling pathway; Regulation; hsa04012
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224.

Key Molecule: Tumor suppressor candidate 7 (TUSC7) [161]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: DESC1/EGFR/AKT signaling pathway; Regulation; hsa04012
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C10 (ABCC10) [150]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal carcinoma [ICD-11: 2B70.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [156], [157]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of miR-296 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs on esophageal cancer cells, and might promote ADR-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of ADR. Down-regulation of miR-296 could significantly decrease the expression of P-glycoprotein, Bcl-2, and the transcription of MDR1, but up-regulate the expression of Bax. And down-regulation of miR-27a significantly decreased expression of MDR1, but did not alter the expression of MRP, miR-27a could possibly mediate drug resistance, at least in part through regulation of MDR1 and apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [149]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PTEN and TNF were demonstrated to be upregulated following miR-187 overexpression. TNF is a cytokine that regulates multiple cellular processes including proliferation and apoptosis. PTEN acts as a tumor suppressor and regulates the PI3k/AkT pathway, which has been identified as a radiation response pathway. The upregulation of PTEN enhances radiosensitivity via the downregulation of the PI3k/AkT pathway.

Key Molecule: Tumor necrosis factor (TNF) [149]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PTEN and TNF were demonstrated to be upregulated following miR-187 overexpression. TNF is a cytokine that regulates multiple cellular processes including proliferation and apoptosis. PTEN acts as a tumor suppressor and regulates the PI3k/AkT pathway, which has been identified as a radiation response pathway. The upregulation of PTEN enhances radiosensitivity via the downregulation of the PI3k/AkT pathway.

Key Molecule: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) [151]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; CCK8 assay
• Mechanism Description: Ectopic overexpression of miR-96 in TE-1 or ECa-109 contributed to tumor growth in xenograft mouse models. Furthermore, up-regulation of miR-96 could reduce the susceptibilities of EC cells to chemotherapy or radiotherapy. RECk was identified as a target of miR-96 and RECk overexpressing could abrogate the growth of EC cells induced by miR-96. Taken together, miR-96 serves as an oncogene role in EC cells through downregulating RECk.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [153]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Key Molecule: Interleukin-6 (IL6) [154]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: IL6/STAT3 signaling signaling pathway; Inhibition; hsa04659
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vitro Model: TE1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: TE11 cells; Esophagus; Homo sapiens (Human); CVCL_1761
• In Vitro Model: TE5 cells; Esophagus; Homo sapiens (Human); CVCL_1764
• In Vitro Model: TE9 cells; Esophagus; Homo sapiens (Human); CVCL_1767
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Let-7c directly repressed cisplatin-activated interleukin (IL) -6/STAT3 prosurvival pathway, restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [160]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Inhibition; hsa04550
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: EC1 cells; Esophagus; Homo sapiens (Human); CVCL_DC74
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Would healing assay; Invasion assay
• Mechanism Description: miR 125a 5p and cisplatin markedly inactivated the STAT3 signaling pathway.

Key Molecule: Transmembrane protease serine 11E (TM11E) [161]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: DESC1/EGFR/AKT signaling pathway; Regulation; hsa04012
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224.

Oesophagogastric cancer [ICD-11: 2B71]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Sphingosine kinase 1 (SPHK1) [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastroesophageal cancer [ICD-11: 2B71.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gastroesophageal cancer tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [20]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastroesophageal cancer [ICD-11: 2B71.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Gastroesophageal cancer tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Gastric cancer [ICD-11: 2B72]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [162]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/MRP1 signaling pathway; Activation; hsa04151
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC-823/DDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric cell cycle assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: LncRNA HOTAIR promotes cisplatin resistance in gastric cancer by targeting miR126 to activate the PI3k/AkT/MRP1 genes.

Key Molecule: hsa-mir-126 [162]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/MRP1 signaling pathway; Activation; hsa04151
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC-823/DDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qRT-PCR; Dual-luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric cell cycle assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: LncRNA HOTAIR promotes cisplatin resistance in gastric cancer by targeting miR126 to activate the PI3k/AkT/MRP1 genes.

Key Molecule: hsa-miR-590-5p [163]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Matrigel transwell assay
• Mechanism Description: miR590-5p regulates gastric cancer cell growth and chemosensitivity through RECk and the AkT/ERk pathway. RECk is a direct target of miR590-5p, knockdown of RECk accelerated cell proliferation and motility and decreased the drug sensitivity.The AkT/ERk and STAT3 signaling pathways were activated by miR590-5p overexpression.

Key Molecule: hsa-mir-27b [164]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/FU cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: LncRNA urothelial carcinoma associated 1 (UCA1) increases multi-drug resistance of gastric cancer via downregulating miR27b.

Key Molecule: Urothelial cancer associated 1 (UCA1) [164]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/FU cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: LncRNA urothelial carcinoma associated 1 (UCA1) increases multi-drug resistance of gastric cancer via downregulating miR27b.

Key Molecule: hsa-mir-34 [165]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Regulation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The downregulation of miR-34a (+) the resistance of human GC cells to DDP treatment through regulation of cell proliferation and apoptosis via the regulation of the MET gene.

Key Molecule: hsa-mir-20a [166]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay
• Mechanism Description: miR-20a directly targeted CYLD, resulting in activation of the NFkB pathway and the downstream targets, livin and survivin, which potentially contributed to GC chemoresistance.

Key Molecule: hsa-mir-363 [167]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-363 promotes gastric cancer cells proliferation by inhibiting FBW7 expression and was associated with chemo-resistance of gastric cancer cells. Silencing FBW7 largely phenocopied miR-363-induced resistance to chemotherapy agents and promoted proliferation in gastric cancer cells. In addition, an inverse correlation between miR-363 and FBW7 mRNA expression was observed in gastric cancer tissues.

Key Molecule: hsa-miR-421 [168]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: N-Myc/ miR421 /ATM signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer by targeting E-cadherin and caspase-3.

Key Molecule: hsa-mir-493 [169]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR493/DKK1 signaling pathway; Regulation; hsa05206
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Dkk1 expression was markedly decreased in GC tissues and serum samples. Dkk1 expression inversely correlated with miR-493 levels and is a direct target of miR-493. Moreover, miR-493 modulated the proliferation, invasion and chemo-sensitivity of GC cells via suppressing Dkk1 expression.

Key Molecule: Pvt1 oncogene (PVT1) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: mTOR/HIF-1alpha /P-gp/MRP1 signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance.PVT-1 was highly expressed in gastric cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. While, PVT1 overexpression exhibit the anti-apoptotic property in BGC823 and SGC7901 cells transfected with LV-PVT1-GFP and treated with cisplatin. Moreover, qRT-PCR and western blotting revealed that PVT1 up-regulation increased the expression of MDR1, MRP, mTOR and HIF-1alpha. Overexpression of LncRNA PVT1 in gastric carcinoma promotes the development of MDR, suggesting an efficacious target for reversing MDR in gastric cancer therapy.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [170]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating LncRNA Ak022798 expression. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Furthermore, we used siRNA to interfere with LncRNA Ak022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased.

Key Molecule: hsa-mir-106a [171]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-106a is up-regulated in the DDP-resistant SGC7901/DDP cells, Overexpression of miR-106a in the SGC7901 cells confers resistance to DDP, PTEN is a target gene of miR-106a, there was a consistent and strong inverse correlation between the miR-106a levels and PTEN, PTEN is a key signal molecule in miR-106a-regulated DDP resistance in SGC7901/DDP cells.

Key Molecule: hsa-mir-20a [172]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGR2 signaling pathway; Inhibition; hsa04625
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NUGC3 cells; Gastric; Homo sapiens (Human); CVCL_1612
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-20a promoted the growth, migration and invasion of GC cells, enhanced the chemoresistance of GC cells to cisplatin and docetaxel. Luciferase activity and Western blot confirmed that miR-20a negatively regulated EGR2 expression. Overexpression of EGR2 significantly attenuated the oncogenic effect of miR-20a.

Key Molecule: hsa-mir-19a [173]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19a/b are upregulated in multidrug-resistant gastric cancer cell line, miR-19a/b suppress the sensitivity of gastric cancer cells to anticancer drugs, miR-19a/b accelerate the efflux of ADR through P-gp upregulation.

Key Molecule: hsa-mir-19b [173]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19a/b are upregulated in multidrug-resistant gastric cancer cell line, miR-19a/b suppress the sensitivity of gastric cancer cells to anticancer drugs, miR-19a/b accelerate the efflux of ADR through P-gp upregulation.

Key Molecule: hsa-mir-21 [174]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell cycle; Inhibition; hsa04110
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The staining of PTEN was reversely correlated with miR-21 levels in tongue squamous cell carcinoma patients, PTEN is an important tumor suppressor gene and the functional inactivation of PTEN by regulation of its expression is relevant to many solid tumors. PETN involved in gastric cancer pathology and its down-regulation can lead to chemotherapeutic drug including cisplatin resistance in gastric cancer patients.

Key Molecule: hsa-mir-200b [36]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: hsa-mir-200c [36]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: hsa-miR-429 [36]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: hsa-mir-200c [175]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NER signaling pathway; Activation; hsa03420
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-200c reverses drug resistance of human gastric cancer cells by targeting regulation of the NER-ERCC3/4 pathway.

Key Molecule: Small nucleolar RNA host gene 5 (SNHG5) [176]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG5 promotes cisplatin resistance in gastric cancer via inhibiting cell apoptosis and upregulating drug resistance-related genes.

Key Molecule: hsa_circ_0000199 [177]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: CircAkT3 regulates PIk3R1 expression, activates the PI3k/AkT signaling pathway and ultimately facilitates CDDP resistance by targeting miR-198 in vitro.

Key Molecule: hsa-miR-198 [177]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Dual-luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Circular RNA AkT3 upregulates PIk3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression.

Key Molecule: hsa-miR-633 [178]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-633 regulates chemotherapy resistance through downregulating FADD in gastric tumor cells.

Key Molecule: Long non-protein coding RNA (XLOC_006753) [179]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA XLOC_006753 promotes the development of multidrug resistance in gastric cancer cells through the PI3k/Akt/mTOR signaling pathway.

Key Molecule: Cancer susceptibility 2 (CASC2) [180]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of CASC2 contributes to cisplatin resistance in gastric cancer by elevating miR-19a expression.

Key Molecule: hsa-mir-19a [180]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of CASC2 contributes to cisplatin resistance in gastric cancer by elevating miR-19a expression.

Key Molecule: hsa-mir-30b [181]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA MALAT1 potentiates autophagy associated cisplatin resistance by suppressing the microRNA 30b/autophagy related gene 5 axis in gastric cancer.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [181]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA MALAT1 potentiates autophagy associated cisplatin resistance by suppressing the microRNA 30b/autophagy related gene 5 axis in gastric cancer.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [182]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: RT-PCR; Luciferase reporter assay; Pull down assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MALAT1 acts as a competing endogenous RNA for miR23b-3p and attenuates the inhibitory effect of miR23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [182]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MALAT1 acts as a competing endogenous RNA for miR23b-3p and attenuates the inhibitory effect of miR23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. MALAT1 regulates autophagy via ATG12.

Key Molecule: hsa-miR-23b-3p [182]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: RT-PCR; Luciferase reporter assay; Pull down assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MALAT1 acts as a competing endogenous RNA for miR23b-3p and attenuates the inhibitory effect of miR23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. MALAT1 promotes autophagy-associated chemoresistance of GC cells via sequestration of miR23b-3p.

Key Molecule: hsa-mir-25 [183]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: microRNA-25 contributes to cisplatin resistance in gastric cancer cells by inhibiting forkhead box O3a.

Key Molecule: hsa-miR-148a-3p [184]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: BGC823CDDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901CDDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; PI/Annexin V-FITC Apoptosis Detection kit assay
• Mechanism Description: miR148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AkAP1 expression level; miR148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. miR148a-3p sensitization of GC cells to CDDP in vivo includes suppression of AkAP1 and RAB12 expression levels.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [185]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FADD/Caspase 8/Caspase 3 signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Colony formation assay; Colony formation assay
• Mechanism Description: Long Noncoding RNA H19/miR675 Axis Promotes Gastric Cancer via FADD/Caspase 8/Caspase 3 signaling Pathway. H19/miR675 targets FADD and inhibits caspase 8/caspase 3, H19 inhibits the expression of FADD through miR675 targeting.

Key Molecule: hsa-mir-675 [185]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FADD/Caspase 8/Caspase 3 signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Colony formation assay; Colony formation assay
• Mechanism Description: Long Noncoding RNA H19/miR675 Axis Promotes Gastric Cancer via FADD/Caspase 8/Caspase 3 signaling Pathway. H19/miR675 targets FADD and inhibits caspase 8/caspase 3, H19 inhibits the expression of FADD through miR675 targeting.

Key Molecule: hsa-mir-145 [186]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-145 exerts tumor-suppressive and chemo-resistance lowering effects by targeting CD44 in gastric cancer.

Key Molecule: hsa-mir-132 [187]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ABCG2 signaling pathway; Activation; hsa02010
• Cell Pathway Regulation: SIRT1/CREB/ABCG2 signaling pathway; Regulation; hsa05200
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulated miR132 in Lgr5+ gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. The expression of miR132 was inversely correlated with SIRT1 in gastric cancer specimens. Down-regulation of SIRT1 led to a subsequent increase of the level of acetylated CREB which in turn activated the ABCG2 signaling pathway.

Key Molecule: hsa-mir-186 [188]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: SGC-7921 cells; Gastric; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The long noncoding RNA PVT1 functions as a competing endogenous RNA by sponging miR186 in gastric cancer.

Key Molecule: Pvt1 oncogene (PVT1) [188]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: SGC-7921 cells; Gastric; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The long noncoding RNA PVT1 functions as a competing endogenous RNA by sponging miR186 in gastric cancer.

Key Molecule: hsa-mir-491 [189]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: TUNEL assay; Clonogenic assay
• Mechanism Description: Inhibition of miR99a and miR491, or overexpress CAPNS1 can enhance cisplatin sensitivity of the resistant cells. miR99a and miR491 might be work as novel molecules regulate cisplatin resistance by directly targeting CAPNS1 associated pathway in human gastric cancer cells.

Key Molecule: hsa-mir-99a [189]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: TUNEL assay; Clonogenic assay
• Mechanism Description: Inhibition of miR99a and miR491, or overexpress CAPNS1 can enhance cisplatin sensitivity of the resistant cells. miR99a and miR491 might be work as novel molecules regulate cisplatin resistance by directly targeting CAPNS1 associated pathway in human gastric cancer cells.

Key Molecule: hsa-miR-613 [190]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Wound healing assay
• Mechanism Description: Elevated expression of miR-613 increased the sensitivity of GC cells to cisplatin and suppressed GC cell proliferation and migration by targeting SOX9.

Key Molecule: hsa-miR-876-3p [191]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Si-TMED3 completely inhibited miR-876-3p inhibitor-stimulated enhancement in cisplatin resistance of cisplatin-resistant GC cells.

Key Molecule: hsa-miR-206 [192]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: MAPK2 signaling pathway; Regulation; hsa04011
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: BGC823/DDP and SGC7901/DDP cell presented lower miR-206 than parental cells, plus higher MAPk3 mRNA or protein.

Key Molecule: hsa-miR-138-5p [193]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Low miR-138-5p levels and high ERCC1 and ERCC4 levels were associated with cisplatin resistance in gastric cancer cells.

Key Molecule: hsa-miR-193a-3p [194]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Inhibition; hsa04217
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: SRSF2, a miR-193a-3p target gene, is downregulated and miR-193a-3p is upregulated, which induces the resistence to cisplatin.

Key Molecule: hsa-miR-135b-5p [195]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: SNU1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: SNU601 cells; Gastric; Homo sapiens (Human); CVCL_0101
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: ATP-Glo cell viability assay
• Mechanism Description: miR-135b-5p protects gastric cancer cells from cisplatin-induced apoptosis and miR-135b-5p overexpression or kLF4 down-regulation lead to cisplatin resistance in gastric cancer cells.

Key Molecule: hsa-mir-30a [196]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-sqPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The IC50 of CDDP in the SGC7901/CDDP-miR-30a mimics group was decreased to 8.56 M (P<0.001 vs. SGC7901/CDDP group), indicating increased chemosensitivity following miR-30a transfectionand the expression of P-gp protein was notably elevated in SGC7901/CDDP cells compared with SGC7901 cells.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [1], [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: HOTAIR recruit the PRC2 complex to silence miR34a via H3k27me3 modification. HOTAIR knockdown inhibited DDP resistance of gastric cancer cells by upregulating miR-34a.

Key Molecule: hsa-mir-34 [1], [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: HOTAIR recruit the PRC2 complex to silence miR34a via H3k27me3 modification. HOTAIR knockdown inhibited DDP resistance of gastric cancer cells by upregulating miR-34a.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [1], [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC-7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: HOTAIR recruit the PRC2 complex to silence miR34a via H3K27me3 modification. HOTAIR knockdown inhibited DDP-resistance of gastric cancer cells by upregulating miR-34a.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: mTOR/HIF-1alpha /P-gp/MRP1 signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance.PVT-1 was highly expressed in gastric cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. While, PVT1 overexpression exhibit the anti-apoptotic property in BGC823 and SGC7901 cells transfected with LV-PVT1-GFP and treated with cisplatin. Moreover, qRT-PCR and western blotting revealed that PVT1 up-regulation increased the expression of MDR1, MRP, mTOR and HIF-1alpha. Overexpression of LncRNA PVT1 in gastric carcinoma promotes the development of MDR, suggesting an efficacious target for reversing MDR in gastric cancer therapy.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: mTOR/HIF-1alpha /P-gp/MRP1 signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance.PVT-1 was highly expressed in gastric cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. While, PVT1 overexpression exhibit the anti-apoptotic property in BGC823 and SGC7901 cells transfected with LV-PVT1-GFP and treated with cisplatin. Moreover, qRT-PCR and western blotting revealed that PVT1 up-regulation increased the expression of MDR1, MRP, mTOR and HIF-1alpha. Overexpression of LncRNA PVT1 in gastric carcinoma promotes the development of MDR, suggesting an efficacious target for reversing MDR in gastric cancer therapy.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [176]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG5 promotes cisplatin resistance in gastric cancer via inhibiting cell apoptosis and upregulating drug resistance-related genes.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [176]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG5 promotes cisplatin resistance in gastric cancer via inhibiting cell apoptosis and upregulating drug resistance-related genes.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [196]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The IC50 of CDDP in the SGC7901/CDDP-miR-30a mimics group was decreased to 8.56 M (P<0.001 vs. SGC7901/CDDP group), indicating increased chemosensitivity following miR-30a transfectionand the expression of P-gp protein was notably elevated in SGC7901/CDDP cells compared with SGC7901 cells.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-21 [197]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: MFC cells; Gastric; Homo sapiens (Human); CVCL_5J48
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; FITC Annexin V Apoptosis Detection assay; Flow cytometric analysis
• Mechanism Description: Exosomal transfer of tumor-associated macrophages derived miR21 confer DDP resistance in gastric cancer Exosomal miR21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3k/AkT signaling pathway by down-regulation of PTEN.

Key Molecule: Phosphatase and tensin homolog (PTEN) [197]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: MFC cells; Gastric; Homo sapiens (Human); CVCL_5J48
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; FITC Annexin V Apoptosis Detection assay; Flow cytometric analysis
• Mechanism Description: Exosomal transfer of tumor-associated macrophages derived miR21 confer DDP resistance in gastric cancer Exosomal miR21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3k/AkT signaling pathway by down-regulation of PTEN.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Calpain small subunit 1 (CAPNS1) [189]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assay; Clonogenic assay
• Mechanism Description: Inhibition of miR99a and miR491, or overexpress CAPNS1 can enhance cisplatin sensitivity of the resistant cells. miR99a and miR491 might be work as novel molecules regulate cisplatin resistance by directly targeting CAPNS1 associated pathway in human gastric cancer cells.

Key Molecule: PI3-kinase regulatory subunit beta (PIK3R2) [162]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/MRP1 signaling pathway; Activation; hsa04151
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC-823/DDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric cell cycle assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: HOTAIR was shown to directly bind to and inhibit miR126 expression and then to promote VEGFA and PIk3R2 expression and activate the PI3k/AkT/MRP1 pathway.

Key Molecule: Vascular endothelial growth factor A (VEGFA) [162]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/MRP0 signaling pathway; Activation; hsa04151
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC-823/DDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric cell cycle assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: HOTAIR was shown to directly bind to and inhibit miR126 expression and then to promote VEGFA and PIk3R2 expression and activate the PI3k/AkT/MRP1 pathway.

Key Molecule: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) [163]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Matrigel transwell assay
• Mechanism Description: miR590-5p regulates gastric cancer cell growth and chemosensitivity through RECk and the AkT/ERk pathway. RECk is a direct target of miR590-5p, knockdown of RECk accelerated cell proliferation and motility and decreased the drug sensitivity.The AkT/ERk and STAT3 signaling pathways were activated by miR590-5p overexpression.

Key Molecule: Hepatocyte growth factor receptor (MET) [165]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Regulation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The downregulation of miR-34a (+) the resistance of human GC cells to DDP treatment through regulation of cell proliferation and apoptosis via the regulation of the MET gene.

Key Molecule: Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD) [166]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay
• Mechanism Description: miR-20a directly targeted CYLD, resulting in activation of the NFkB pathway and the downstream targets, livin and survivin, which potentially contributed to GC chemoresistance.

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [167]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-363 promotes gastric cancer cells proliferation by inhibiting FBW7 expression and was associated with chemo-resistance of gastric cancer cells. Silencing FBW7 largely phenocopied miR-363-induced resistance to chemotherapy agents and promoted proliferation in gastric cancer cells. In addition, an inverse correlation between miR-363 and FBW7 mRNA expression was observed in gastric cancer tissues.

Key Molecule: Caspase-3 (CASP3) [168]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: N-Myc/ miR421 /ATM signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• Experiment for Molecule Alteration: Western blot analysis; Flow cytometric assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer by targeting E-cadherin and caspase-3.

Key Molecule: Cadherin-1 (CDH1) [168]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: N-Myc/ miR421 /ATM signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• Experiment for Molecule Alteration: Western blot analysis; Flow cytometric assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-421 promoted metastasis, inhibited apoptosis, and induced cisplatin resistance in gastric cancer by targeting E-cadherin and caspase-3.

Key Molecule: Dickkopf-related protein 1 (DKK1) [169]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR493/DKK1 signaling pathway; Regulation; hsa05206
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Dkk1 expression was markedly decreased in GC tissues and serum samples. Dkk1 expression inversely correlated with miR-493 levels and is a direct target of miR-493. Moreover, miR-493 modulated the proliferation, invasion and chemo-sensitivity of GC cells via suppressing Dkk1 expression.

Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: mTOR/HIF-1alpha /P-gp/MRP1 signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance.PVT-1 was highly expressed in gastric cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. While, PVT1 overexpression exhibit the anti-apoptotic property in BGC823 and SGC7901 cells transfected with LV-PVT1-GFP and treated with cisplatin. Moreover, qRT-PCR and western blotting revealed that PVT1 up-regulation increased the expression of MDR1, MRP, mTOR and HIF-1alpha. Overexpression of LncRNA PVT1 in gastric carcinoma promotes the development of MDR, suggesting an efficacious target for reversing MDR in gastric cancer therapy.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: mTOR/HIF-1alpha /P-gp/MRP1 signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance.PVT-1 was highly expressed in gastric cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. While, PVT1 overexpression exhibit the anti-apoptotic property in BGC823 and SGC7901 cells transfected with LV-PVT1-GFP and treated with cisplatin. Moreover, qRT-PCR and western blotting revealed that PVT1 up-regulation increased the expression of MDR1, MRP, mTOR and HIF-1alpha. Overexpression of LncRNA PVT1 in gastric carcinoma promotes the development of MDR, suggesting an efficacious target for reversing MDR in gastric cancer therapy.

Key Molecule: Caspase-3 (CASP3) [170]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating LncRNA Ak022798 expression. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Furthermore, we used siRNA to interfere with LncRNA Ak022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased.

Key Molecule: Caspase-8 (CASP8) [170]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating LncRNA Ak022798 expression. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Furthermore, we used siRNA to interfere with LncRNA Ak022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased.

Key Molecule: E3 SUMO-protein ligase EGR2 (EGR2) [172]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGR2 signaling pathway; Inhibition; hsa04625
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NUGC3 cells; Gastric; Homo sapiens (Human); CVCL_1612
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-20a promoted the growth, migration and invasion of GC cells, enhanced the chemoresistance of GC cells to cisplatin and docetaxel. Luciferase activity and Western blot confirmed that miR-20a negatively regulated EGR2 expression. Overexpression of EGR2 significantly attenuated the oncogenic effect of miR-20a.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [36]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [36]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3) [175]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NER signaling pathway; Activation; hsa03420
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-200c reverses drug resistance of human gastric cancer cells by targeting regulation of the NER-ERCC3/4 pathway.

Key Molecule: DNA repair endonuclease XPF (ERCC4) [175]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NER signaling pathway; Activation; hsa03420
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-200c reverses drug resistance of human gastric cancer cells by targeting regulation of the NER-ERCC3/4 pathway.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [176]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG5 promotes cisplatin resistance in gastric cancer via inhibiting cell apoptosis and upregulating drug resistance-related genes.

Key Molecule: Apoptosis regulator BAX (BAX) [176]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG5 promotes cisplatin resistance in gastric cancer via inhibiting cell apoptosis and upregulating drug resistance-related genes.

Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1) [177]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: CircAkT3 regulates PIk3R1 expression, activates the PI3k/AkT signaling pathway and ultimately facilitates CDDP resistance by targeting miR-198 in vitro.

Key Molecule: FAS-associated death domain protein (FADD) [178]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-633 regulates chemotherapy resistance through downregulating FADD in gastric tumor cells.

Key Molecule: Autophagy protein 5 (ATG5) [181]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA MALAT1 potentiates autophagy associated cisplatin resistance by suppressing the microRNA 30b/autophagy related gene 5 axis in gastric cancer.

Key Molecule: Ubiquitin-like protein ATG12 (ATG12) [182]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MALAT1 acts as a competing endogenous RNA for miR23b-3p and attenuates the inhibitory effect of miR23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. MALAT1 regulates autophagy via ATG12.

Key Molecule: Forkhead box protein O3 (FOXO3) [183]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: microRNA-25 contributes to cisplatin resistance in gastric cancer cells by inhibiting forkhead box O3a.

Key Molecule: A-kinase anchor protein 1 (AKAP1) [184]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: BGC823CDDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901CDDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; PI/Annexin V-FITC Apoptosis Detection kit assay
• Mechanism Description: miR148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AkAP1 expression level; miR148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. miR148a-3p sensitization of GC cells to CDDP in vivo includes suppression of AkAP1 and RAB12 expression levels.

Key Molecule: Ras-related protein Rab-12 (RAB12) [184]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: BGC823CDDP cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: SGC7901CDDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; PI/Annexin V-FITC Apoptosis Detection kit assay
• Mechanism Description: miR148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AkAP1 expression level; miR148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. miR148a-3p sensitization of GC cells to CDDP in vivo includes suppression of AkAP1 and RAB12 expression levels.

Key Molecule: FAS-associated death domain protein (FADD) [185]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FADD/Caspase 8/Caspase 3 signaling pathway; Regulation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Colony formation assay; Colony formation assay
• Mechanism Description: Long Noncoding RNA H19/miR675 Axis Promotes Gastric Cancer via FADD/Caspase 8/Caspase 3 signaling Pathway. FADD, a significant gene regulating cell apoptosis, is a direct target of miR675. H19/miR675 targets FADD and inhibits caspase 8/caspase 3, H19 inhibits the expression of FADD through miR675 targeting.

Key Molecule: Extracellular matrix receptor III (CD44) [186]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-145 exerts tumor-suppressive and chemo-resistance lowering effects by targeting CD44 in gastric cancer.

Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A) [188]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: SGC-7921 cells; Gastric; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: PVT1 knockdown suppressed the HIF-1alpha mRNA and protein expression levels of HIF-1alpha in BGC-823 cells, PVT1 promoted the HIF-1alpha expression by regulating miR186.

Key Molecule: Transcription factor SOX-9 (SOX9) [190]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Wound healing assay
• Mechanism Description: Elevated expression of miR-613 increased the sensitivity of GC cells to cisplatin and suppressed GC cell proliferation and migration by targeting SOX9.

Key Molecule: Transmembrane emp24 domain-containing protein 3 (TMED3) [191]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Si-TMED3 completely inhibited miR-876-3p inhibitor-stimulated enhancement in cisplatin resistance of cisplatin-resistant GC cells.

Key Molecule: Mitogen-activated protein kinase 3 (MAPK3) [192]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: MAPK2 signaling pathway; Regulation; hsa04011
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry assay
• Mechanism Description: BGC823/DDP and SGC7901/DDP cell presented lower miR-206 than parental cells, plus higher MAPk3 mRNA or protein.

Key Molecule: DNA excision repair protein ERCC-1 (ERCC1) [193]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Low miR-138-5p levels and high ERCC1 and ERCC4 levels were associated with cisplatin resistance in gastric cancer cells.

Key Molecule: DNA repair endonuclease XPF (ERCC4) [193]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Low miR-138-5p levels and high ERCC1 and ERCC4 levels were associated with cisplatin resistance in gastric cancer cells.

Key Molecule: Serine/arginine-rich splicing factor 2 (SRSF2) [194]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Inhibition; hsa04217
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: SRSF2, a miR-193a-3p target gene, is downregulated and miR-193a-3p is upregulated, which induces the resistence to cisplatin.

Key Molecule: Krueppel-like factor 4 (KLF4) [195]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: SNU1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: SNU601 cells; Gastric; Homo sapiens (Human); CVCL_0101
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: ATP-Glo cell viability assay
• Mechanism Description: miR-135b-5p protects gastric cancer cells from cisplatin-induced apoptosis and miR-135b-5p overexpression or kLF4 down-regulation lead to cisplatin resistance in gastric cancer cells.

Key Molecule: Sphingosine kinase 1 (SPHK1) [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cardia adenocarcinoma [ICD-11: 2B72.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [1], [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RIP experiments assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: Phosphatase and tensin homolog (PTEN) [171], [173], [174]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-106a is up-regulated in the DDP-resistant SGC7901/DDP cells, Overexpression of miR-106a in the SGC7901 cells confers resistance to DDP, PTEN is a target gene of miR-106a, there was a consistent and strong inverse correlation between the miR-106a levels and PTEN, PTEN is a key signal molecule in miR-106a-regulated DDP resistance in SGC7901/DDP cells.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [20]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cardia adenocarcinoma [ICD-11: 2B72.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-524-5p [198]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: AZ521 cells; Gastric; Homo sapiens (Human); CVCL_2862
• In Vitro Model: SC-M1 cells; Gastric; Homo sapiens (Human); CVCL_G299
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell cell migration assay
• Mechanism Description: Upregulation of microRNA-524-5p enhances the cisplatin sensitivity of gastric cancer cells by modulating proliferation and metastasis via targeting SOX9, SOX9 overexpression could counteracts the chemosensitizing effects of miR524-5p.

Key Molecule: hsa-mir-30a [199]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysiss
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: EMT is associated with cisplatin resistance in gastric cancer. miR-30a is an important miRNA modulating EMT and cisplatin sensitivity of SGC-7901 and SGC-7901/DDP cells.

Key Molecule: hsa-mir-181a [200]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901/CDDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-181a inhibited autophagy in cisplatin-resistant cell line SGC7901/CDDP. ATG5 was a potential target of miR-181a. miR-181a sensitized SGC7901/CDDP cells to cisplatin in vivo and in vitro.

Key Molecule: hsa-mir-101 [201]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry analysis assay
• Mechanism Description: miR-101 inhibits proliferation and promotes DDP-induced apoptosis of SGC7901/DDP cells via negatively mediating the expression of VEGF-C, which facilitate gastric cancer cells sensitivity to Cisplatin.

Key Molecule: hsa-mir-29b [202]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression of miR-29b was significantly upregualted by cisplatin treatment,while its target gene AkT2 was downregulated. The up-regulation of miR-29b (+) the sensitivity of gastric cancer cells to cisplatin,while the knock-down of miR-29b (+) the cisplatin resistance. Rescue experiments demonstrated that the miR-29b might regulate cisplatin resistance of gastric cancer cell by targeting PI3k/Akt pathway. The expressions of the other two members of miR-29 family, miR-29a/c, were promoted by cisplatin treatment,but they had no significant effect on gastric cancer cell's resistance to cisplatin.

Key Molecule: hsa-mir-26a [203]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: NRAS and E2F2 as the direct targets of miR-26a were further confirmed in luciferase activity assays and miR-26a-mediated these two genes expression analysis. Our results also found that knockdown of NRAS or E2F2 sensitize GC cells to cisplatin. miR-26a overexpression has been demonstrated to improve the sensitivity of GC cells to cisplatin and this effect was considered to be mediated via its targets NRAS and E2F2.

Key Molecule: hsa-miR-23b-3p [204]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR23b-3p/ATG12/HMGB2/autophagy regulatory loop signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: SCID-SHO mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Key Molecule: Long non-protein coding RNA (AK022798) [170]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Inhibition; hsa04330
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating LncRNA Ak022798 expression. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Furthermore, we used siRNA to interfere with LncRNA Ak022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [170]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Inhibition; hsa04330
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating LncRNA Ak022798 expression. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Furthermore, we used siRNA to interfere with LncRNA Ak022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased.

Key Molecule: hsa-mir-218 [205]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 kit assay
• Mechanism Description: miR-218 increased chemosensitivity of gastric cancer cells to cisplatin via its target mTOR inhibitor.

Key Molecule: hsa-mir-503 [206]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Clonogenic assay
• Mechanism Description: miR-503 was significantly downregulated in gastric cancer tissues and several gastric cancer cell lines. Additionally, downregulation of miR-503 in the cisplatin (DDP)-resistant gastric cancer cell line SGC7901/DDP was concurrent with the upregulation of insulin-like growth factor-1 receptor (IGF1R) and B-cell lymphoma 2 (BCL2) expression compared with the parental SGC7901 cell line. An in vitro drug sensitivity assay showed that overexpression of miR-503 sensitized SGC7901/DDP cells to cisplatin. The luciferase activity of reporters driven by IGF1R and BCL2 3'-untranslated regions in SGC7901/DDP cells suggested that IGF1R and BCL2 were both direct target genes of miR-503. Enforced miR-503 expression in SGC7901/DDP cells reduced expression of the target proteins, inhibited proliferation, and sensitized the cells to DDP-induced apoptosis.

Key Molecule: hsa-mir-1271 [207]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Regulation; hsa04212
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Enforced miR-1271 expression repressed the protein levels of its targets, inhibited proliferation of SGC7901/DDP cells, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Overall, on the basis of the results of our study, we proposed that miR-1271 could regulate cisplatin resistance in human gastric cancer cells, at least partially, via targeting the IGF1R/IRS1 pathway.

Key Molecule: hsa-mir-185 [208]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue exclusion assay; Tunel assay
• Mechanism Description: Restoration of miR-185 alone can inhibit gastric cancer tumor growth. Moreover, combination therapy using enforced miR-185 expression and lower dose chemotherapeutic drugs had an effective therapeutic activity against large established tumors, with decreased host toxicity. miR-185 increases the chemosensitivity of gastric cancer cells in vitro and in vivo. It exerts tumor-suppressing function through negatively regulating ARC. Besides, miR-185 upregulation in response to cisplatin or doxorubicin treatment in gastric cancer cells is dependent on RUNX3 transcriptional activity.

Key Molecule: hsa-mir-141 [209]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown miR-141 expression in 7901/DDP and 7901 cells could significantly improve cisplatin sensitivity. Over-expression of miR-141 resulted in (+) resistance to cisplatin in both gastric cancer cells. We also demonstrated that miR-141 directly targets kEAP1 by luciferase reporter assay, and that down-regulation of kEAP1 induces cisplatin resistance. Conversely, over-expression of kEAP1 significantly (+) cisplatin sensitivity. Our 75 pairs of tissues also showed that kEAP1 was significantly up-regulated in H. pylori-positive tissues.

Key Molecule: hsa-mir-34 [210]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT/survivin signaling pathway; Inhibition; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-34aexpression was down-regulated in cisplatin-resistant cell lines.miR-34a over-expression could improve the sensitivity ofgastric cancer cells against cisplatin-based chemotherapies,with PI3k/AkT/survivin signaling pathway possibly involvedin the mechanism.

Key Molecule: hsa-miR-508-5p [211]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1.

Key Molecule: hsa-mir-200c [212]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The knockdown of RhoE enhanced the sensitivity of SGC7901/DDP cells and changed expres-sion of some genes. Transfection of pre-miR-200c reduces RhoEexpression. miRNA-200cregulated the sensitivity of chemotherapy to cisplatin(DDP) in gastric cancer by possibly targeting RhoE.

Key Molecule: hsa-mir-497 [213]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Enforced miR-497 expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, has-miR-497 could play a role in both gastric and lung cancer cell lines at least in part by modulation of apoptosis via targeting BCL2.

Key Molecule: hsa-mir-181 [214]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Key Molecule: hsa-mir-34 [215]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Human gastric cancer kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor, miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth.

Key Molecule: hsa-mir-15b [216]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-15b and miR-16, among the downregulated miRNAs in SGC7901/VCR cells, were demonstrated to play a role in the development of MDR in gastric cancer cells by targeting the antiapoptotic gene BCL2.

Key Molecule: hsa-mir-16 [216]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-15b and miR-16, among the downregulated miRNAs in SGC7901/VCR cells, were demonstrated to play a role in the development of MDR in gastric cancer cells by targeting the antiapoptotic gene BCL2.

Key Molecule: hsa-miR-574-3p [217]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric carcinoma [ICD-11: 2B72.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-574-3p regulates epithelial mesenchymal transition and cisplatin resistance via targeting ZEB1 in human gastric carcinoma cells.

Key Molecule: hsa-mir-320 [218]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Overexpression of miR320a inhibited tumor growth in vitro and in vivo and increased the sensitivity of GC cells to cisplatin by targeting ADAM10.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [3]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Caspase-3 activity detection; MTT assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: hsa-mir-34 [3]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual-luciferase report assay; RNA immunoprecipitation (RIP) assay; qRT-PCR
• Experiment for Drug Resistance: Caspase-3 activity detection; MTT assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: hsa-mir-101 [219]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: p38/MAPK/AKT signaling pathway; Regulation; hsa04010
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR101 alleviates chemoresistance of gastric cancer cells by targeting ANXA2, ectopic expression of ANXA2 reversed the effect of miR101 on P-gp expression, cell viability and apoptosis. knockdown of ANXA2 increased sensitivity to doxorubicin, 5-FU and DDP by regulating p38MAPk and AkT pathways.

Key Molecule: hsa-mir-200c [220]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BIRC6/p53-mediated apoptosis signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: ZEB2 signaling pathway; Inhibition; hsa05202
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-200c regulates cisplatin resistance by targeting ZEB2 in human gastric cancer cells.

Key Molecule: hsa-miR-33b-5p [221]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
• Mechanism Description: miR33b-5p sensitizes gastric cancer cells to chemotherapy drugs via inhibiting HMGA2 expression.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [187]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SIRT1/CREB/ABCG2 signaling pathway; Regulation; hsa05200
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulated miR132 in Lgr5+ gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [222]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Silencing LncRNA HULC could enhance chemotherapy induced apoptosis in GC cells.

Key Molecule: hsa-mir-129 [223]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Intrinsic apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR129 reversed cisplatin-resistance through inhibiting the P-gp expression in GC cells. miR129 activated the intrinsic apoptotic pathway via upregulating caspase-9 and caspase-3.

Key Molecule: hsa-mir-874 [224]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 874 could inhibit autophagy and sensitize GC cells to chemotherapy via the target gene ATG16L1.

Key Molecule: hsa-mir-495 [225]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2.

Key Molecule: hsa-miR-17-5p [226]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of miR-17-5p reverses drug resistance of gastric cancer cells and increases p21 expression in SGC7901/DDP cells.

Key Molecule: hsa-mir-149 [227]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-149 enhances SGC7901/DDP cell sensitivity to cisplatin by downregulating FoxM1 expression.

Key Molecule: hsa-mir-125b [228]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-125b improved the chemosensitivity of DDP in HGC-27 and MGC-803 cells and miR-125b obviously inhibited the expression of HER2 at protein level in HGC-27 and MGC-803 cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [211]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [187]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SIRT1/CREB/ABCG2 signaling pathway; Regulation; hsa05200
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulated miR132 in Lgr5+ gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [223]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Intrinsic apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR129 reversed cisplatin-resistance through inhibiting the P-gp expression in GC cells. miR129 activated the intrinsic apoptotic pathway via upregulating caspase-9 and caspase-3.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-30a [229]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR30a can decrease multidrug resistance (MDR) of gastric cancer cells, miR30a overexpression decreased the expression of P-gp, a MDR-related protein. It is also an important miRNA modulating EMT of the cancer cells.

Key Molecule: Death effector domain-containing protein (DEDD) [230]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-17 may have tumor suppressive effects on GC and enhance its chemosensitivity by promoting DEDD, impairing EMT in GC cells.

Key Molecule: hsa-mir-17 [230]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-17 may have tumor suppressive effects on GC and enhance its chemosensitivity by promoting DEDD, impairing EMT in GC cells.

Key Molecule: Catenin beta-1 (CTNNB1) [231]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay; Flow cytometry assay
• Mechanism Description: Silencing of ZFAS1 augmented the sensitivity to cis-platinum or paclitaxel in gastric cancer cancer cells and silencing of ZFAS1-induced inhibition of malignancies was reversed by beta-catenin.

Key Molecule: ZNFX1 antisense RNA 1 (ZFAS1) [231]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay; Flow cytometry assay
• Mechanism Description: Silencing of ZFAS1 augmented the sensitivity to cis-platinum or paclitaxel in gastric cancer cancer cells and silencing of ZFAS1-induced inhibition of malignancies was reversed by beta-catenin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor SOX-9 (SOX9) [198]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: AZ521 cells; Gastric; Homo sapiens (Human); CVCL_2862
• In Vitro Model: SC-M1 cells; Gastric; Homo sapiens (Human); CVCL_G299
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell cell migration assay
• Mechanism Description: Upregulation of microRNA-524-5p enhances the cisplatin sensitivity of gastric cancer cells by modulating proliferation and metastasis via targeting SOX9, SOX9 overexpression could counteracts the chemosensitizing effects of miR524-5p.

Key Molecule: Autophagy protein 5 (ATG5) [200]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901/CDDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-181a inhibited autophagy in cisplatin-resistant cell line SGC7901/CDDP. ATG5 was a potential target of miR-181a. miR-181a sensitized SGC7901/CDDP cells to cisplatin in vivo and in vitro.

Key Molecule: Vascular endothelial growth factor C (VEGFC) [201]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry analysis assay
• Mechanism Description: miR-101 inhibits proliferation and promotes DDP-induced apoptosis of SGC7901/DDP cells via negatively mediating the expression of VEGF-C, which facilitate gastric cancer cells sensitivity to Cisplatin.

Key Molecule: RAC-beta serine/threonine-protein kinase (AKT2) [202]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression of miR-29b was significantly upregualted by cisplatin treatment,while its target gene AkT2 was downregulated. The up-regulation of miR-29b (+) the sensitivity of gastric cancer cells to cisplatin,while the knock-down of miR-29b (+) the cisplatin resistance. Rescue experiments demonstrated that the miR-29b might regulate cisplatin resistance of gastric cancer cell by targeting PI3k/Akt pathway. The expressions of the other two members of miR-29 family, miR-29a/c, were promoted by cisplatin treatment,but they had no significant effect on gastric cancer cell's resistance to cisplatin.

Key Molecule: Transcription factor E2F2 (E2F2) [203]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: NRAS and E2F2 as the direct targets of miR-26a were further confirmed in luciferase activity assays and miR-26a-mediated these two genes expression analysis. Our results also found that knockdown of NRAS or E2F2 sensitize GC cells to cisplatin. miR-26a overexpression has been demonstrated to improve the sensitivity of GC cells to cisplatin and this effect was considered to be mediated via its targets NRAS and E2F2.

Key Molecule: GTPase Nras (NRAS) [203]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: NRAS and E2F2 as the direct targets of miR-26a were further confirmed in luciferase activity assays and miR-26a-mediated these two genes expression analysis. Our results also found that knockdown of NRAS or E2F2 sensitize GC cells to cisplatin. miR-26a overexpression has been demonstrated to improve the sensitivity of GC cells to cisplatin and this effect was considered to be mediated via its targets NRAS and E2F2.

Key Molecule: Ubiquitin-like protein ATG12 (ATG12) [204]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR23b-3p/ATG12/HMGB2/autophagy regulatory loop signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Key Molecule: High mobility group protein B2 (HMGB2) [204]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR23b-3p/ATG12/HMGB2/autophagy regulatory loop signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [205]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Expression
• Experiment for Drug Resistance: WST-1 kit assay
• Mechanism Description: miR-218 increased chemosensitivity of gastric cancer cells to cisplatin via its target mTOR inhibitor.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [207]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Regulation; hsa04212
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: Enforced miR-1271 expression repressed the protein levels of its targets, inhibited proliferation of SGC7901/DDP cells, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Overall, on the basis of the results of our study, we proposed that miR-1271 could regulate cisplatin resistance in human gastric cancer cells, at least partially, via targeting the IGF1R/IRS1 pathway.

Key Molecule: Insulin receptor substrate 1 (IRS1) [207]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Regulation; hsa04212
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Wound Healing assay; Matrigel transmembrane invasion assay
• Mechanism Description: Enforced miR-1271 expression repressed the protein levels of its targets, inhibited proliferation of SGC7901/DDP cells, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Overall, on the basis of the results of our study, we proposed that miR-1271 could regulate cisplatin resistance in human gastric cancer cells, at least partially, via targeting the IGF1R/IRS1 pathway.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [207]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Regulation; hsa04212
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: Enforced miR-1271 expression repressed the protein levels of its targets, inhibited proliferation of SGC7901/DDP cells, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Overall, on the basis of the results of our study, we proposed that miR-1271 could regulate cisplatin resistance in human gastric cancer cells, at least partially, via targeting the IGF1R/IRS1 pathway.

Key Molecule: Activity-regulated cytoskeleton-associated protein (ARC) [208]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay; Tunel assay
• Mechanism Description: Restoration of miR-185 alone can inhibit gastric cancer tumor growth. Moreover, combination therapy using enforced miR-185 expression and lower dose chemotherapeutic drugs had an effective therapeutic activity against large established tumors, with decreased host toxicity. miR-185 increases the chemosensitivity of gastric cancer cells in vitro and in vivo. It exerts tumor-suppressing function through negatively regulating ARC. Besides, miR-185 upregulation in response to cisplatin or doxorubicin treatment in gastric cancer cells is dependent on RUNX3 transcriptional activity.

Key Molecule: Kelch-like ECH-associated protein 1 (KEAP1) [209]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown miR-141 expression in 7901/DDP and 7901 cells could significantly improve cisplatin sensitivity. Over-expression of miR-141 resulted in (+) resistance to cisplatin in both gastric cancer cells. We also demonstrated that miR-141 directly targets kEAP1 by luciferase reporter assay, and that down-regulation of kEAP1 induces cisplatin resistance. Conversely, over-expression of kEAP1 significantly (+) cisplatin sensitivity. Our 75 pairs of tissues also showed that kEAP1 was significantly up-regulated in H. pylori-positive tissues.

Key Molecule: DNA-directed RNA polymerase I subunit RPA12 (RPA12) [211]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1.

Key Molecule: Rho-related GTP-binding protein RhoE (RND3) [212]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The knockdown of RhoE enhanced the sensitivity of SGC7901/DDP cells and changed expres-sion of some genes. Transfection of pre-miR-200c reduces RhoEexpression. miRNA-200cregulated the sensitivity of chemotherapy to cisplatin(DDP) in gastric cancer by possibly targeting RhoE.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [214]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [215]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Human gastric cancer kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor, miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [215]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Human gastric cancer kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor, miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth.

Key Molecule: Neurogenic locus notch homolog protein (NOTCH) [215]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Human gastric cancer kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor, miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [216]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-15b and miR-16, among the downregulated miRNAs in SGC7901/VCR cells, were demonstrated to play a role in the development of MDR in gastric cancer cells by targeting the antiapoptotic gene BCL2.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [217]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric carcinoma [ICD-11: 2B72.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-574-3p regulates epithelial mesenchymal transition and cisplatin resistance via targeting ZEB1 in human gastric carcinoma cells.

Key Molecule: Mammalian disintegrin-metalloprotease (ADAM10) [218]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter activity assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Overexpression of miR320a inhibited tumor growth in vitro and in vivo and increased the sensitivity of GC cells to cisplatin by targeting ADAM10.

Key Molecule: Annexin A2 (ANXA2) [219]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: p38/MAPK/AKT signaling pathway; Regulation; hsa04010
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RIP assay; Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR101 alleviates chemoresistance of gastric cancer cells by targeting ANXA2, ectopic expression of ANXA2 reversed the effect of miR101 on P-gp expression, cell viability and apoptosis. knockdown of ANXA2 increased sensitivity to doxorubicin, 5-FU and DDP by regulating p38MAPk and AkT pathways.

Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2) [220]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ZEB2 signaling pathway; Inhibition; hsa05202
• In Vitro Model: SGC7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-200c regulates cisplatin resistance by targeting ZEB2 in human gastric cancer cells.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [221]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometric apoptosis assay
• Mechanism Description: miR33b-5p sensitizes gastric cancer cells to chemotherapy drugs via inhibiting HMGA2 expression.

Key Molecule: Autophagy-related protein 16-1 (ATG16L1) [224]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 874 could inhibit autophagy and sensitize GC cells to chemotherapy via the target gene ATG16L1.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [225]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2.

Key Molecule: Ribonuclease P protein subunit p21 (RPP21) [226]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of miR-17-5p reverses drug resistance of gastric cancer cells and increases p21 expression in SGC7901/DDP cells.

Key Molecule: Forkhead box protein M1 (FOXM1) [227]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-149 enhances SGC7901/DDP cell sensitivity to cisplatin by downregulating FoxM1 expression.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [228]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-125b improved the chemosensitivity of DDP in HGC-27 and MGC-803 cells and miR-125b obviously inhibited the expression of HER2 at protein level in HGC-27 and MGC-803 cells.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [207], [206]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R signaling pathway; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Regulation; hsa04212
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Clonogenic assay
• Mechanism Description: Enforced miR-1271 expression repressed the protein levels of its targets, inhibited proliferation of SGC7901/DDP cells, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Overall, on the basis of the results of our study, we proposed that miR-1271 could regulate cisplatin resistance in human gastric cancer cells, at least partially, via targeting the IGF1R/IRS1 pathway. and miR-503 was significantly downregulated in gastric cancer tissues and several gastric cancer cell lines. Additionally, downregulation of miR-503 in the cisplatin (DDP)-resistant gastric cancer cell line SGC7901/DDP was concurrent with the upregulation of insulin-like growth factor-1 receptor (IGF1R) and B-cell lymphoma 2 (BCL2) expression compared with the parental SGC7901 cell line. An in vitro drug sensitivity assay showed that overexpression of miR-503 sensitized SGC7901/DDP cells to cisplatin. The luciferase activity of reporters driven by IGF1R and BCL2 3'-untranslated regions in SGC7901/DDP cells suggested that IGF1R and BCL2 were both direct target genes of miR-503. Enforced miR-503 expression in SGC7901/DDP cells reduced expression of the target proteins, inhibited proliferation, and sensitized the cells to DDP-induced apoptosis.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-155 [33]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Adrenaline increased miR-155 expression in an NFkB dependent manner. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to cisplatin induced apoptosis. In contrast, HT29 cells overexpressing miR-155 inhibitor displayed decreased cell proliferation and sensitivity to cisplatin induced cell death. In summary, our study here revealed that adrenaline-NFkB-miR-155 pathway at least partially contributes to the psychological stress induced proliferation and chemoresistance in HT29 cells.

Key Molecule: hsa-mir-155 [232]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vivo Model: miR-155 knockout mouse model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay; Caspase 3 activity assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-155 was associated with decreased levels of FOXO3, primarily through inhibiting the expression of FOXO3 to increase colon cancer resistanec to cisplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [232]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vivo Model: miR-155 knockout mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Caspase 3 activity assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-155 was associated with decreased levels of FOXO3, primarily through inhibiting the expression of FOXO3 to increase colon cancer resistanec to cisplatin.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA 261 (LINC00261) [233]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LINC00261 down-regulated beta-catenin in nuclei and promoted beta-catenin degradation, i.ctivated Wnt/beta-catenin pathway and downstream target genes, then inhibited TCF/LEF/beta-catenin complex formation, and finally, repressed colon cancer and reduced the cisplatin resistance of tumor cells.

Key Molecule: hsa-mir-101 [234]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; AO/EB double staining; Transwell invasion assay
• Mechanism Description: Upregulation of miR101 enhances the cytotoxic effect of anticancer drugs through inhibition of colon cancer cell proliferation. The upregulated expression of miR101 inhibited proliferation and migration, and increased the sensitivity of colon cancer cells to chemotherapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [233]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: Cell metastasis; Inhibition; hsa05205
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LINC00261 down-regulated beta-catenin in nuclei and promoted beta-catenin degradation, i.ctivated Wnt/beta-catenin pathway and downstream target genes, then inhibited TCF/LEF/beta-catenin complex formation, and finally, repressed colon cancer and reduced the cisplatin resistance of tumor cells.

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-153 [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; Soft agar colony forming ability assay; Flow cytometry assay
• Mechanism Description: miR-153 promoted invasiveness indirectly by inducing MMP9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor FOXO3a.

Key Molecule: hsa-mir-1271 [235]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-1271 enhances the sensitivity of colorectal cancer cells to cisplatin via downregulating mTOP.

Key Molecule: hsa-mir-199a [236]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: ALDHA1+ CCSCs cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: ALDHA1 cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay
• Mechanism Description: Upregulation of miR199a/b contributes to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. Gsk3beta was the direct target of miR199a/b, miR199a/b regulates Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ CCSCs.

Key Molecule: hsa-mir-199b [236]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: ALDHA1+ CCSCs cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: ALDHA1 cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay
• Mechanism Description: Upregulation of miR199a/b contributes to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. Gsk3beta was the direct target of miR199a/b, miR199a/b regulates Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ CCSCs.

Key Molecule: Pvt1 oncogene (PVT1) [237]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Intrinsic apoptotic signaling pathway; Inhibition; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: PVT1 involved in cisplatin resistance of CRC cells via upregulation of drug resistance-associated molecules, including multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1), by blocking the intrinsic apoptotic pathway.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [237]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Intrinsic apoptotic signaling pathway; Inhibition; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: PVT1 involved in cisplatin resistance of CRC cells via upregulation of drug resistance-associated molecules, including multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1), by blocking the intrinsic apoptotic pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [7]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay; Soft agar colony forming ability assay; Flow cytometry assay
• Mechanism Description: miR-153 promoted invasiveness indirectly by inducing MMP9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor FOXO3a.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [235]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-1271 enhances the sensitivity of colorectal cancer cells to cisplatin via downregulating mTOP.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [236]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: ALDHA1+ CCSCs cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: ALDHA1 cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry; Luciferase reporter assay
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay
• Mechanism Description: Upregulation of miR199a/b contributes to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. Gsk3beta was the direct target of miR199a/b, miR199a/b regulates Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ CCSCs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-497 [238]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: HCT28 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: IGF1-R has an important role in mediating activation of the PI3k/Akt pathway, miR-497 inhibits PI3k/Akt signalling. Down-regulation of miR-497 is an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.

Key Molecule: hsa-mir-148a [239]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Inhibition; hsa04520
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-148a suppressed expression of stem cell markers, inhibited sphere formation, invasion and migration, induced apoptosis, and reduced chemo-resistance in cisplatin-resistant SW480 cells while suppressing WNT10b expression and beta-catenin signaling activities.

Key Molecule: hsa-mir-20a [240]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: ROS/ASk1/JNk signaling pathway; Activation; hsa04071
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of miR-20a enhanced sensitivity of colorectal cancer cells to cisplatin through the ROS/ASk1/JNk pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [238]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: HCT28 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: IGF1-R has an important role in mediating activation of the PI3k/Akt pathway, miR-497 inhibits PI3k/Akt signalling. Down-regulation of miR-497 is an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.

Key Molecule: Protein Wnt-10b (WNT10B) [239]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Inhibition; hsa04520
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-148a suppressed expression of stem cell markers, inhibited sphere formation, invasion and migration, induced apoptosis, and reduced chemo-resistance in cisplatin-resistant SW480 cells while suppressing WNT10b expression and beta-catenin signaling activities.

Key Molecule: Mitogen-activated protein kinase kinase kinase 5 (MAP3K5) [240]

• Molecule Alteration: Phosphorylation; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: ROS/ASk1/JNk signaling pathway; Activation; hsa04071
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of miR-20a enhanced sensitivity of colorectal cancer cells to cisplatin through the ROS/ASk1/JNk pathway.

Rectal cancer [ICD-11: 2B92]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (LINC00461) [27]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Rectal cancer [ICD-11: 2B92.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR-593-5p/CCND1 signaling pathway; Regulation; hsa05206
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: SW837 cells; Colon; Homo sapiens (Human); CVCL_1729
• In Vitro Model: SW1463 cells; Rectum; Homo sapiens (Human); CVCL_1718
• In Vitro Model: HR8348 cells; Salivary glands; Homo sapiens (Human); CVCL_W821
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LINC00461 mediates cisplatin resistance of rectal cancer by targeting miR-593-5p/CCND1 axis, shedding new light on the treatment of rectal cancer.LINC00461 expression was upregulated in rectal cancer cells. LINC00461 depletion restrained rectal cancer progression and sensitized rectal cancer cells to cisplatin. Molecular mechanism assays testified that LINC00461 bound with miR-593-5p. Besides, miR-593-5p upregulation improved the sensitivity of rectal cancer cells to cisplatin. Additionally, cyclin D1 (CCND1) was manifested to be a downstream target of miR-593-5p. Furthermore, CCND1 upregulation could reverse the effect of LINC00461 downregulation on rectal cancer progression and cisplatin resistance of rectal cancer.

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-374b [45]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BxPC3-R cells; Pancreas; Homo sapiens (Human); CVCL_XX78
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Resazurin conversion assay
• Mechanism Description: The computational prediction that downregulation of miR-374b likely contributed to the acquisition of resistance to cisplatin in BxPC3-R cells was experimentally tested by transfection of miR-374b into BxPC3-R cells and subsequently measuring cisplatin sensitivity of these cells relative to controls. The results demonstrated that miR-374b transfection significantly reduced drug resistance in BxPC3-R cells to levels approaching those of the parental BxPC3 cells.

Liver cancer [ICD-11: 2C12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-363 [241]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR363/Mcl-1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy decreased miR-363 expression in HCC patients. miR-363 expression was also lower in HepG2-R cells than in HepG2 cells, which indicated that the downregulation of miR-363 may be related to cisplatin resistance. overexpression of miR-363 by its mimics can effectively increase the sensitivity of cisplatin-resistant HepG2 cells to cisplatin-induced apoptosis. overexpression of miR-363 could inhibit the expression of Mcl-1 in HepG2-R cells, which implied the inverse correlation between the expression of miR-363 and Mcl-1. More importantly, enforced exogenous Mcl-1 significantly attenuated apoptosis induced by cisplatin. All these results support that Mcl-1 is the target of miR-363 which can enhance sensitivity of human cisplatin-resistant HCC cell cisplatin at least partially.

Key Molecule: hsa-mir-182 [242]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR182/TP53INP1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-182 levels are significantly increased in HCC patients treated with cisplatin-based chemotherapy. Upregulated miR-182 inhibits TP53INP1 expression, which results in sequent cisplatin resistance.

Key Molecule: hsa-mir-146a [38]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [38]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [38]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [38]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [38]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-130a [243]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell adhesion; Inhibition; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Oncogenic activation of the Wnt/beta-catenin signaling pathway is common in HCC. Upregulated miR-130a inhibited RUNX3 expression, which resulted in activation of Wnt/beta-catenin signaling and sequent cisplatin resistance.

Key Molecule: hsa-miR-199a-5p [15]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-199a-5p levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. Downregulated miR-199a-5p enhanced autophagy activation by targeting ATG7. Cisplatin-induced downregulation of miR-199a-5p increases cell proliferation by activating autophagy.

Key Molecule: hsa-mir-33a [244]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Colorectal neoplasia differentially expressed (CRNDE) [244]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: hsa-miR-613 [245]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: SOX9 signaling pathway; Activation; hsa04024
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.

Key Molecule: Long non-protein coding RNA (RP11-134G8.8) [246]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, the LncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

Key Molecule: Novel transcript, overlapping ACER2 (RP11-363E7.4) [246]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, the LncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

Key Molecule: ENSG00000267194 (RP1-193H18.2 ) [246]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, the LncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [247]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cytotoxicity; Inhibition; hsa04650
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: xCELLigence assay
• Mechanism Description: HULC promotes the phosphorylation of YB-1 through the extracellular signal-regulated kinase pathway, in turn leads to the release of YB-1 from its bound mRNA.

Key Molecule: Long non-protein coding RNA (NRAL) [248]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NRAL/miR340-5p/Nrf2 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: There is mutual inhibition between NRAL and mir-340-5p and NRAL directly interacts with miR-340-5p to up-regulate the expression of its target, Nrf2, to mediate cisplatin-resistant HCC phenotypes.

Key Molecule: hsa-miR-340-5p [248]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NRAL/miR340-5p/Nrf2 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: There is mutual inhibition between NRAL and mir-340-5p and NRAL directly interacts with miR-340-5p to up-regulate the expression of its target, Nrf2, to mediate cisplatin-resistant HCC phenotypes.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [249], [250]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [250]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis; RNAi assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of HOTAIR expression downregulated the MRP1 expression levels in the k562-imatinib cells and resulted in higher sensitivity to the imatinib treatment. In addition, the activation of PI3k/Akt was greatly attenuated when HOTAIR was knocked down in k562-imatinib cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [241]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR363/Mcl-1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy decreased miR-363 expression in HCC patients. miR-363 expression was also lower in HepG2-R cells than in HepG2 cells, which indicated that the downregulation of miR-363 may be related to cisplatin resistance. overexpression of miR-363 by its mimics can effectively increase the sensitivity of cisplatin-resistant HepG2 cells to cisplatin-induced apoptosis. overexpression of miR-363 could inhibit the expression of Mcl-1 in HepG2-R cells, which implied the inverse correlation between the expression of miR-363 and Mcl-1. More importantly, enforced exogenous Mcl-1 significantly attenuated apoptosis induced by cisplatin. All these results support that Mcl-1 is the target of miR-363 which can enhance sensitivity of human cisplatin-resistant HCC cell cisplatin at least partially.

Key Molecule: Tumor protein p53-inducible nuclear protein 1 (TP53INP1) [242]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR182/TP53INP1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-182 levels are significantly increased in HCC patients treated with cisplatin-based chemotherapy. Upregulated miR-182 inhibits TP53INP1 expression, which results in sequent cisplatin resistance.

Key Molecule: Runt-related transcription factor 3 (RUNX3) [243]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Oncogenic activation of the Wnt/beta-catenin signaling pathway is common in HCC. Upregulated miR-130a inhibited RUNX3 expression, which resulted in activation of Wnt/beta-catenin signaling and sequent cisplatin resistance.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [15]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-199a-5p levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. Downregulated miR-199a-5p enhanced autophagy activation by targeting ATG7. Cisplatin-induced downregulation of miR-199a-5p increases cell proliferation by activating autophagy.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [244]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Luciferase activity assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Transcription factor SOX-9 (SOX9) [245]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: SOX9 signaling pathway; Activation; hsa04024
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.

Key Molecule: Y-box-binding protein 1 (YBX1) [247]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: xCELLigence assay
• Mechanism Description: HULC promotes the phosphorylation of YB-1 through the extracellular signal-regulated kinase pathway, in turn leads to the release of YB-1 from its bound mRNA.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [249], [250]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Activation; hsa04110
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-133a [251]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-miR-326 [251]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-mir-27b [252]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: hsa-mir-340 [253]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Nrf2 signaling pathway; Activation; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bioinformatics analysis and luciferase assays ofNrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR-340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitorsreactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively,the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistancein hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

Key Molecule: Beclin-1 (BECN1) [254]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepS cells; Liver; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: hsa-mir-30a [254]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: hsa-mir-30a [254]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepS cells; Liver; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: TPTE pseudogene 1 (TPTEP1) [255]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IL6/STAT3 signaling signaling pathway; Inhibition; hsa04659
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: LncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [250]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3/ABCB1 signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: hsa-mir-503 [256]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 may enhance the sensitivity of BEL-7402 cells to cisplatin and inhibit the cell proliferation by targeting bcl-2. miR503 could interact with bcl-2 and inhibit its expression.

Key Molecule: hsa-miR-199a-3p [257]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. miR199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma.

Key Molecule: hsa-miR-33a-5p [258]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HSPA8 was the direct downstream target gene for miR33a-mediated drug resistance. Inhibition of miR33a-5p expression reduced cisplatin sensitivity in Hep3B and 97L and increased their drug resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [257]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. miR199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [251]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: Cyclin-G1 (CCNG1) [252]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: NFE2-related factor 2 (NRF2) [253]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Nrf2 signaling pathway; Activation; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bioinformatics analysis and luciferase assays ofNrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR-340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitorsreactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively,the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistancein hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

Key Molecule: Beclin-1 (BECN1) [254]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: NFE2-related factor 2 (NRF2) [259]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KkU-100 cells; Gallbladder; Homo sapiens (Human); CVCL_3996
• In Vitro Model: KkU-M156 cells; Gallbladder; Homo sapiens (Human); CVCL_M260
• In Vitro Model: KkU-M213 cells; Gallbladder; Homo sapiens (Human); CVCL_M261
• In Vitro Model: KkU-M214 cells; Gallbladder; Homo sapiens (Human); CVCL_M264
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Acri-dine orange and ethidium bromide (AO/EB) fluorescent dyes assay
• Mechanism Description: Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant, cytoprotective, and metabolic enzymes, plays important roles in drug resistance and proliferation in cancer cells. Nrf2 mRNA expression of kkU-M156 and kkU-100 cells, representatives of low and high-Nrf2-expressing CCA cells, were silenced using siRNA. After knockdown of Nrf2, the sensitivity of those cells to the cytotoxicity of cisplatin (Cis) was enhanced in association with the increased release of AIF and downregulation of Bcl-xl in both cells.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [250]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3/ABCB1 signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [256]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase activity assay; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 may enhance the sensitivity of BEL-7402 cells to cisplatin and inhibit the cell proliferation by targeting bcl-2. miR503 could interact with bcl-2 and inhibit its expression.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [257]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. miR199a-3p could increase the cisplatin sensitivity of cholangiocarcinoma cell lines by regulating mTOR expression.

Key Molecule: Heat shock cognate 71 kDa protein (HSPA8) [258]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HSPA8 was the direct downstream target gene for miR33a-mediated drug resistance. Inhibition of miR33a-5p expression reduced cisplatin sensitivity in Hep3B and 97L and increased their drug resistance.

Gallbladder cancer [ICD-11: 2C13]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-31 [260]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gallbladder cancer [ICD-11: 2C13.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR31/Src/AKT/Bax/BCL2 signaling pathway; Inhibition; hsa05206
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: NOZ cells; Gallbladder; Homo sapiens (Human); CVCL_3079
• In Vitro Model: GBC-SD/DDP cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: NOZ/DDP cells; Gallbladder; Homo sapiens (Human); CVCL_3079
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony forming assay
• Mechanism Description: miR31 regulates the cisplatin resistance by targeting Src in gallbladder cancer The Src/Akt/Bax/Bcl-2 signaling cascade could be activated in the miR31-downregulated DDP-resistant GBC cells, and downregulation of Src sensitized the miR31 expressing GBC cells to DDP.

Key Molecule: hsa-miR-125b-5p [261]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gallbladder cancer [ICD-11: 2C13.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR125b-5p/BCL2 signaling pathway; Regulation; hsa05206
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: NOZ cells; Gallbladder; Homo sapiens (Human); CVCL_3079
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; Annexin V/PI Apoptosis Detection assay
• Mechanism Description: miR125b-5p enhances chemotherapy sensitivity to cisplatin by down-regulating Bcl2 in gallbladder cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase Src (SRC) [260]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gallbladder cancer [ICD-11: 2C13.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR31/Src/AKT/Bax/BCL2 signaling pathway; Inhibition; hsa05206
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: NOZ cells; Gallbladder; Homo sapiens (Human); CVCL_3079
• In Vitro Model: GBC-SD/DDP cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: NOZ/DDP cells; Gallbladder; Homo sapiens (Human); CVCL_3079
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony forming assay
• Mechanism Description: miR31 regulates the cisplatin resistance by targeting Src in gallbladder cancer The Src/Akt/Bax/Bcl-2 signaling cascade could be activated in the miR31-downregulated DDP-resistant GBC cells, and downregulation of Src sensitized the miR31 expressing GBC cells to DDP.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [261]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gallbladder cancer [ICD-11: 2C13.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR125b-5p/BCL2 signaling pathway; Regulation; hsa05206
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: NOZ cells; Gallbladder; Homo sapiens (Human); CVCL_3079
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Annexin V/PI Apoptosis Detection assay
• Mechanism Description: miR125b-5p enhances chemotherapy sensitivity to cisplatin by down-regulating Bcl2 in gallbladder cancer.

Laryngeal cancer [ICD-11: 2C23]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Laryngeal squamous cell carcinoma [ICD-11: 2C23.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: AMC-HN-8 cells; Larynx; Homo sapiens (Human); CVCL_5966
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR and EZH2 were over-expressed in LSCC tissue. The higher expression was significantly related to T phase, pathological grades, and risk of lymphatic metastasis of LSCC. Suppressing HOTAIR expression stimulated EZH2 expressing, promoted the proliferation of AMC-HN8 cells, and increased the sensitivity to cis-platinum of the LSCC cells.

Key Molecule: Long non-protein coding RNA, p53 induced transcript (LINC-PINT) [262]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Laryngeal carcinoma [ICD-11: 2C23.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hedgehog signaling pathway; Regulation; hsa04340
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA LINC-PINT regulates laryngeal carcinoma cell stemness and chemoresistance through miR-425-5p/PTCH1/SHH axis.

Key Molecule: hsa-miR-425-5p [262]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Laryngeal carcinoma [ICD-11: 2C23.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hedgehog signaling pathway; Regulation; hsa04340
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA LINC-PINT regulates laryngeal carcinoma cell stemness and chemoresistance through miR-425-5p/PTCH1/SHH axis.

Key Molecule: hsa-mir-17 [37]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Laryngeal squamous cell carcinoma [ICD-11: 2C23.10]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: miR17/ATG7 signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA BLACAT1 Can enhance ATG7 expression by suppressing miR-17 expression to promote autophagy and cisplatin resistance in non small cell lung cancer through the miR-17/ATG7 signaling pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Laryngeal squamous cell carcinoma [ICD-11: 2C23.10]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: AMC-HN-8 cells; Larynx; Homo sapiens (Human); CVCL_5966
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR and EZH2 were over-expressed in LSCC tissue. The higher expression was significantly related to T phase, pathological grades, and risk of lymphatic metastasis of LSCC. Suppressing HOTAIR expression stimulated EZH2 expressing, promoted the proliferation of AMC-HN8 cells, and increased the sensitivity to cis-platinum of the LSCC cells.

Key Molecule: Protein patched homolog 1 (PTCH1) [262]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Laryngeal carcinoma [ICD-11: 2C23.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hedgehog signaling pathway; Regulation; hsa04340
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA LINC-PINT regulates laryngeal carcinoma cell stemness and chemoresistance through miR-425-5p/PTCH1/SHH axis.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125a [263]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC apoptosis assay
• Mechanism Description: Inhibition of HAX-1 by miR125a reverses cisplatin resistance in laryngeal cancer stem cells. Overexpression of miR125a increases the sensitivity of Hep-2-CSCs to cisplatin by inhibiting HAX-1.

Key Molecule: hsa-mir-133a [264]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Laryngeal carcinoma [ICD-11: 2C23.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: NP69 cells; Nasopharynx; Homo sapiens (Human); CVCL_F755
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hep-2v cells persistently express high levels of ATP7B, and cisplatin treatment stimulates increased ATP7B expression of ATP7B in these cells. ATP7B contributes to the removal of intracellular cisplatin to the extracellular space, thereby promoting cell survival. However, ATP7B expression was significantly decreased following exogenous expression of miR-133a. Reduced levels of ATP7B likely impaired the transportation of cisplatin to the extracellular space, thereby increasing the sensitivity of Hep-2v cells to cisplatin.

Key Molecule: Polycomb complex protein BMI-1 (BMI1) [265]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: AMC-HN-8 cells; Larynx; Homo sapiens (Human); CVCL_5966
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR128a decreases the expression of BMI1 and suppresses the resistance of laryngeal cancer cells to paclitaxel & cisplatin.

Key Molecule: hsa-mir-128a [265]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: AMC-HN-8 cells; Larynx; Homo sapiens (Human); CVCL_5966
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR128a decreases the expression of BMI1 and suppresses the resistance of laryngeal cancer cells to paclitaxel & cisplatin.

Key Molecule: hsa-mir-17 [266]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Laryngeal squamous cell carcinoma [ICD-11: 2C23.10]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: lncRNA-XIST/miR17 axis; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of LncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. LncRNA-XIST inhibits the expression of miR17 to modulate ATG7 and LncRNA-XIST regulates autophagy through ATG7.

Key Molecule: hsa-mir-26b [267]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR26b decreases the cisplatin-resistance in laryngeal cancer by targeting ATF2. miR26b in Hep-2/R decreased the expression of ATF2, and thus inhibiting the phosphorylation of ATF2 and formation of cellular ATF2-c-Jun complex induced by cisplatin. As the results, Hep-2/R cells failed to overexpress the Bcl-xl which is a key anti-apoptotic protein under the cisplatin treatment. Therefore, overexpression of miR26b was found to be able to promote mitochondrial apoptosis induced by cisplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: HCLS1-associated protein X-1 (HAX1) [263]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC apoptosis assay
• Mechanism Description: Inhibition of HAX-1 by miR125a reverses cisplatin resistance in laryngeal cancer stem cells. Overexpression of miR125a increases the sensitivity of Hep-2-CSCs to cisplatin by inhibiting HAX-1.

Key Molecule: Copper-transporting ATPase 2 (ATP7B) [264]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Laryngeal carcinoma [ICD-11: 2C23.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: NP69 cells; Nasopharynx; Homo sapiens (Human); CVCL_F755
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hep-2v cells persistently express high levels of ATP7B, and cisplatin treatment stimulates increased ATP7B expression of ATP7B in these cells. ATP7B contributes to the removal of intracellular cisplatin to the extracellular space, thereby promoting cell survival. However, ATP7B expression was significantly decreased following exogenous expression of miR-133a. Reduced levels of ATP7B likely impaired the transportation of cisplatin to the extracellular space, thereby increasing the sensitivity of Hep-2v cells to cisplatin.

Key Molecule: Cyclic AMP-dependent transcription factor ATF-2 (ATF2) [267]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Laryngeal cancer [ICD-11: 2C23.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR26b decreases the cisplatin-resistance in laryngeal cancer by targeting ATF2. miR26b in Hep-2/R decreased the expression of ATF2, and thus inhibiting the phosphorylation of ATF2 and formation of cellular ATF2-c-Jun complex induced by cisplatin. As the results, Hep-2/R cells failed to overexpress the Bcl-xl which is a key anti-apoptotic protein under the cisplatin treatment. Therefore, overexpression of miR26b was found to be able to promote mitochondrial apoptosis induced by cisplatin.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione synthetase (GSH) [268]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Vi-cell cell viability analyzer assay
• Mechanism Description: miR-21 achieves the drug resistance effect through three mechanisms: Increasing MDR1 and MPR1 expression levels, and enhancing drug efflux from the cells; increasing GSH, superoxide dismutase and GST-Pi expression levels and promoting drug inactivation; and inhibiting the PI3k signaling pathway and in turn inhibiting apoptotic signaling.

Key Molecule: Glutathione S-transferase P (GSTP1) [268]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Vi-cell cell viability analyzer assay
• Mechanism Description: miR-21 achieves the drug resistance effect through three mechanisms: Increasing MDR1 and MPR1 expression levels, and enhancing drug efflux from the cells; increasing GSH, superoxide dismutase and GST-Pi expression levels and promoting drug inactivation; and inhibiting the PI3k signaling pathway and in turn inhibiting apoptotic signaling.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-451 [269]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR451/Mcl1/DPP signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DPP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT and cytotoxicity (IC50) assays
• Mechanism Description: miR451 enhanced DPP chemosensitivity of lung cancer cells by negatively regulating Mcl-1 in vitro and in vivo.

Key Molecule: hsa-mir-141 [270]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay and TUNEL assay
• Mechanism Description: miR-141 expression was significantly up-regulated in cisplatin-resistant A549/DDP cells compared with the parental cell line A549; and PDCD4, an important apoptosis regulator, was found to be down-regulated. Luciferase activity assay and Western blot analysis confirmed that PDCD4 is a direct target of miR-141. Inhibition of miR-141 in A549/DDP cells markedly increased cisplatin sensitivity and apoptosis, which was partially abrogated by PDCD4 inhibition, indicating that PDCD4 is a functional target of miR-141 in of the regulation of cisplatin sensitivity.

Key Molecule: Growth arrest specific 5 (GAS5) [271]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: GAS5 downregulation is associated with cisplatin resistance in NSCLC. GAS5 can inhibit autophagy and therefore enhance cisplatin sensitivity in NSCLC cells.

Key Molecule: Maternally expressed 3 (MEG3) [272]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway.The present study detected that the expression levels of Meg3 were significantly lower in cisplatin-resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. The results of the present study also demonstrated that the Meg3-mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, beta-catenin and survivin, which is a target gene of the WNT/beta-catenin signaling pathway.

Key Molecule: hsa-mir-10a [273]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TGF-beta/Smad2/STAT3/STAT5 signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-10a had an important role in promoting drug resistance in tumors through enhancing drug efflux and inhibiting apoptosis via upregulation of MDR1, MRP1 and RhoE expression. In addition, miR-10a promoted the expression of TGF-beta as wells as regulated the activity of the Smad2/STAT3/STAT5 pathway and its downstream transcriptional factors of HIF and eIF4E, which may be the potential mechanism of drug resistance in A549 cells. Therefore, miR-10a may be an important drug target for improving cancer treatment; however, further studies are required to explore the clinical applications of miR-10a inhibitors.

Key Molecule: hsa-mir-106a [274]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 106a expression levels were upregulated in the DDP-resistant cell line A549/DDP compared with its parental cell line, A549. miR 106a-transfection induced DDP resistance in A549 cells, while repression of miR 106a by anti miR 106a in A549/DDP resulted in (+) DDP cytotoxicity. Furthermore, it was discovered that the mechanism of miR 106a induced DDP resistance involved the expression of adenosine triphosphatase binding cassette, sub family A, member 1 (ABCA1), as indicated by transfection of cells with short interfering RNA-ABCA1.

Key Molecule: hsa-mir-21 [268]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Vi-cell cell viability analyzer assay
• Mechanism Description: miR-21 achieves the drug resistance effect through three mechanisms: Increasing MDR1 and MPR1 expression levels, and enhancing drug efflux from the cells; increasing GSH, superoxide dismutase and GST-Pi expression levels and promoting drug inactivation; and inhibiting the PI3k signaling pathway and in turn inhibiting apoptotic signaling.

Key Molecule: hsa-mir-182 [275]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression level of miR-182 in A549 cell line was significantly higher than that in NHBE cell line. Transfection of miR-182 inhibitor induced sensitivity of A549 cells to cisplatin. A549 cells transfected with PDCD4 siRNA became more resistant to cisplatin therapy. We found an increase PDCD4 protein level following the transfection of miR-182 inhibitor using Western blot analysis. In addition, the (+) growth-inhibitory effect by miR-182 inhibitor was weakened after the addition of PDCD4 siRNA.

Key Molecule: hsa-mir-224 [276]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Intrinsic mitochondrial death signaling pathway; Inhibition; hsa4210)
• Cell Pathway Regulation: p21; Regulation
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-224 could promote the in vitro and in vivo DDP resistance of LA cells via regulating G1/S cell cycle transition and apoptosis. p21WAF1/CIP1, a potent cyclin-dependent kinase inhibitor, was identified as the direct and functional target gene of miR-224. Overexpression of p21WAF1/CIP1 could phenocopy the effect of miR-224 downregulation and silencing of p21WAF1/CIP1 could partially reverse the effect of miR-224 downregulation on DDP resistance of DDP-resistant LA cells. In addition, miR-224 could affect the G1/S transition of cell cycle and apoptosis in LA cells through the p21WAF1/CIP1-pRb pathway and the intrinsic mitochondrial death pathway. Furthermore, miR-224 was found to be downregulated in DDP-responding LA tissues, and its expression was inversely correlated with p21WAF1/CIP1. Multivariate analyses indicated that the status of miR-224 might be an independent prognostic factor for predicting the survival of LA patients.

Key Molecule: hsa-mir-192 [277]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-192 induced Cisplatin-resistance and inhibited cell apoptosis in lung cancer via negative targeting Bim expression.

Key Molecule: hsa-mir-100 [278]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: NCI-H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of HOXA1 in immortalised human mammary epithelial cells results in oncogenic transformation and tumour formation in vivo. HOXA1 expression was inversely correlated with miR-100. HOXA1-mediated SCLC chemoresistance is under the regulation of miR-100. HOXA1 may be a prognostic predictor and potential therapeutic target in human SCLC.

Key Molecule: hsa-mir-146a [279]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cytotoxicity detection kit
• Mechanism Description: For human lung cancer cells, RIP1 plays a role in survival. RIP1 knockdown enhanced cytotoxicity induced by the frontline therapeutic drug cisplatin, which is associated with increased miRNA-146a, reduced catalase expression, ROS induction, and degradation of antiapoptotic IAP proteins.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [280]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression.

Key Molecule: hsa-mir-31 [281]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: LTEP-a-2 cells; Lung; Homo sapiens (Human); CVCL_6929
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-31 is inversely correlated with ABCB9 expression in NSCLC cells. ABCB9 is a direct target of miR-31. Ectopic expression of miR-31 confers DDP-induced apoptosis. Inhibition of ABCB9 is required for DDP resistance.

Key Molecule: hsa-mir-205 [282]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN signaling pathway; Regulation; hsa05235
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-205 promotes the growth of the NSCLC cell lines, miR-205 is inversely correlated with PTEN expression, miR-205 has the ability to promote growth, migration, invasion and chemoresistance of NSCLC cells by targeting PTEN.

Key Molecule: Long non-protein coding RNA (AC090952.4.1) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Long non-protein coding RNA (AK126698) [283]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Microarray assay; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of beta-catenin not only plays a role in the NSCLC tumorigenesis but also increases chemoresistance. NkD2 inhibits beta-catenin by binding to Dvl protein. knockdown Ak126698 in A549 will decreased expression of NkD2, increased expression of whole beta-catenin and nuclear translocation of beta-catenin.

Key Molecule: Long non-protein coding RNA 210 (LINC00210) [283]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Long non-protein coding RNA (AK123263) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Long non-protein coding RNA (AK126698) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Carboxylesterase 1 pseudogene 1 (CES1P1) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Novel transcript (RP3-508I15.14) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Long non-protein coding RNA 1589 (LINC01589) [283]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: hsa-mir-128 [284]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 clone 23 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1299 clone 41 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The expression of the transcriptional repressor E2F5, a target of miR-128-2, strongly decreases after miR-128-2 exogenous expression. This leads to the abrogation of E2F5 repressive activity on p21waf1 promoter and, consequently, to the transcriptional induction of p21waf1. The newly synthesized p21waf1 protein is mainly localized into the cytoplasmic compartment, where it exerts an anti-apoptotic function in response to anticancer drug treatments.

Key Molecule: hsa-mir-200b [36]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: hsa-mir-200c [36]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: hsa-miR-429 [36]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: hsa_circ_0001946 [285]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: Nucleotide excision repair signaling pathway; Activation; hsa03420
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Hsa_circ_0001946 Inhibits Lung Cancer Progression and Mediates Cisplatin Sensitivity in Non-small Cell Lung Cancer via the Nucleotide Excision Repair Signaling Pathway.

Key Molecule: MBNL1 antisense RNA 1 (MBNL1-AS1) [286]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: LncRNA MBNL1-AS1 restoration could decelerate the occurrence and progression of NSCLC, thereby highlighting the functionality of LncRNA MBNL1-AS1 restoration as a sponge of miR-301b-3p to suppress the proliferation, invasion, drug resistance, and sphere formation of CSC cells in NSCLC via upregulation of TGFBR2.

Key Molecule: hsa-miR-301b-3p [286]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: LncRNA MBNL1-AS1 restoration could decelerate the occurrence and progression of NSCLC, thereby highlighting the functionality of LncRNA MBNL1-AS1 restoration as a sponge of miR-301b-3p to suppress the proliferation, invasion, drug resistance, and sphere formation of CSC cells in NSCLC via upregulation of TGFBR2.

Key Molecule: ITGA6 antisense RNA 1 (ITGA6-AS1) [287]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Deregulation of LncRNA-AC078883.3 and microRNA-19a is involved in the development of chemoresistance to cisplatin via modulating signaling pathway of PTEN/AkT.

Key Molecule: hsa-mir-19a [287]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Deregulation of LncRNA-AC078883.3 and microRNA-19a is involved in the development of chemoresistance to cisplatin via modulating signaling pathway of PTEN/AkT.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [288]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: MALAT1 could alter chemo-resistance (Cisplatin, Adriamycin, Gefitinib and Paclitaxel) of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.

Key Molecule: hsa-miR-197-3p [288]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: MALAT1 could alter chemo-resistance (Cisplatin, Adriamycin, Gefitinib and Paclitaxel) of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [289]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: H3kH3k27me3 induces multidrug resistance in small cell lung cancer by affecting HOXA1 DNA methylation via regulation of the LncRNA HOTAIR.

Key Molecule: hsa-mir-223 [290]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: IGF1R/AKT/PI3K signaling pathway; Activation; hsa05224
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H838 cells; Lung; Homo sapiens (Human); CVCL_1594
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA EGFR-AS1 Can enhance IGF1R expression by suppressing miR-223 expression to promotes cisplatin resistance in the non-small cell lung cancer.

Key Molecule: EGFR antisense RNA 1 (EGFR-AS1) [290]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: IGF1R/AKT/PI3K signaling pathway; Activation; hsa05224
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H838 cells; Lung; Homo sapiens (Human); CVCL_1594
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA EGFR-AS1 Can enhance IGF1R expression by suppressing miR-223 expression to promotes cisplatin resistance in the non-small cell lung cancer.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [290]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: IGF1R/AKT/PI3K signaling pathway; Activation; hsa05224
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H838 cells; Lung; Homo sapiens (Human); CVCL_1594
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA EGFR-AS1 Can enhance IGF1R expression by suppressing miR-223 expression to promotes cisplatin resistance in the non-small cell lung cancer.

Key Molecule: BLACAT1 overlapping LEMD1 locus (BLACAT1) [37]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: miR17/ATG7 signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA BLACAT1 Can enhance ATG7 expression by suppressing miR-17 expression to promote autophagy and cisplatin resistance in non small cell lung cancer through the miR-17/ATG7 signaling pathway.

Key Molecule: hsa-mir-216a [291]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR216a.

Key Molecule: hsa-miR-5100 [292]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CD44/CD133 assay; MTT assay
• Mechanism Description: miR5100 increases the cisplatin resistance of the lung cancer stem cells by inhibiting the Rab6. miR5100 increases cisplatin resistance via the mitochondrial apoptosis pathway.

Key Molecule: X inactive specific transcript (XIST) [266]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of LncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. LncRNA-XIST inhibits the expression of miR17 to modulate ATG7 and LncRNA-XIST regulates autophagy through ATG7.

Key Molecule: MIR4435-2 host gene (MIR4435-2HG) [293]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: LncRNA Ak001796 increased the resistance of NSCLC cells to cisplatin through regulating cell apoptosis and cell proliferation.

Key Molecule: ENSG00000247844 (CCAT1) [294]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: DDP-resistant NSCLC A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA CCAT1/miR130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. CCAT1 effectively acted as a miRNA sponge for miR130a-3p to enhance SOX4 expression.

Key Molecule: ENSG00000247844 (CCAT1) [294]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: DDP-resistant NSCLC A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA CCAT1/miR130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. CCAT1 effectively acted as a miRNA sponge for miR130a-3p to enhance SOX4 expression.

Key Molecule: hsa-miR-130a-3p [294]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: DDP-resistant NSCLC A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA CCAT1/miR130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. CCAT1 effectively acted as a miRNA sponge for miR130a-3p to enhance SOX4 expression.

Key Molecule: X inactive specific transcript (XIST) [295]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometric analysis; TUNEL assay; MTT assay; Colony formation assay
• Mechanism Description: LncRNA XIST overexpression in A549 cells increased their chemosensitivity to cisplatin both in vitro and in vivo by protecting cells from apoptosis and promoting cell proliferation. XIST functioned as competing endogenous RNA to repress let-7i, which controlled its down-stream target BAG-1.

Key Molecule: hsa-mir-181c [296]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: H1299/DDP cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR181c contributed to DDP resistance in NSCLC cells through activation of the Wnt/beta-catenin pathway by targeting WIF1. miR181c egatively regulates the expression of WIF1, anti-miR181c suppressed the Wnt/beta-catenin pathway by regulating WIF1.

Key Molecule: hsa-miR-106b-5p [297]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR106b-5p enhanced the sensitivity of A549/DDP cells to cisplatin by targeting the expression of PkD2.

Key Molecule: Growth arrest specific 5 (GAS5) [298]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR21/PTEN signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: GAS5 could compete with PTEN for miR21 binding, GAS5 downregulation can induce trastuzumab resistance of breast cancer.

Key Molecule: Growth arrest specific 5 (GAS5) [298]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: GAS5 could compete with PTEN for miR21 binding, GAS5 downregulation can induce trastuzumab resistance of breast cancer By negatively regulating the intracellular levels of PI3k, PTEN exerts a suppressive effect on tumor through AkT pathway. GAS5 regulated NSCLC chemo-sensitivity to DDP-based therapy through PTEN pathway.

Key Molecule: hsa-mir-21 [298]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Regulation; hsa04151
• Cell Pathway Regulation: miR21/PTEN signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: miR21 acts as an oncogenic miRNA through targeting PTEN in many cancers. By negatively regulating the intracellular levels of PI3k, PTEN exerts a suppressive effect on tumor through AkT pathway. miR21 was involved in GAS5 regulation of NSCLC sensitivity to DDP through PTEN pathway.

Key Molecule: hsa-miR-146a-5p [299]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR146a-5p increases chemosensitivity of NSCLC to cisplatin by targeting Atg12 to inhibit autophagy.

Key Molecule: hsa-mir-488 [300]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NER signaling pathway; Activation; hsa03420
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Cell Titer 96 AQueous One Solution Assay; Annexin V FITC Apoptosis assay; Clone formation assay
• Mechanism Description: miRNA-488 inhibited eIF3a expression by directly binding to the 3'UTR of eIF3a, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC).

Key Molecule: HOX transcript antisense RNA (HOTAIR) [301]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Elevated HOTAIR expression is associated with drug resistance in NSCLC patients and is related to klf4 upregulation.

Key Molecule: hsa-miR-1236-3p [302]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: pim-3 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: PR-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulation of miR-1236-3p could reverse DDP resistance in lung cancer cells through targeting TPT1 and inhibition of the Pim-3 signaling pathway.

Key Molecule: hsa-miR-144-3p [303]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-144-3p promotes cisplatin sensitivity by downregulating Nrf2 in lung cancer cells.

Key Molecule: TatD DNase domain containing 1 (TATDN1) [304]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TATDN1 enhanced the DDP-tolerance of NSCLC cells by upregulating TRIM66 expression via sponging miR-451.

Key Molecule: hsa-mir-451 [304]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TATDN1 enhanced the DDP-tolerance of NSCLC cells by upregulating TRIM66 expression via sponging miR-451.

Key Molecule: hsa-mir-328 [305]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miRNA 328 overexpression confers cisplatin resistance in non small cell lung cancer via targeting of PTEN.

Key Molecule: Serine/threonine-protein kinase DCLK1 (DCLK1) [306]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-539 enhances chemosensitivity to cisplatin in non-small cell lung cancer by targeting DCLk1.

Key Molecule: hsa-mir-539 [306]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-539 enhances chemosensitivity to cisplatin in non-small cell lung cancer by targeting DCLk1.

Key Molecule: hsa-mir-221 [307]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell senescence; Inhibition; hsa04218
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; SA-beta-gal assay
• Mechanism Description: Suppression of miR-221 could lead to increase of PTEN expression level and enhance the CDDP chemosensitivity.

Key Molecule: hsa-mir-146a [308]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA 146a promotes chemotherapy resistance in lung cancer cells by targeting DNA damage inducible transcript 3 (CHOP).

Key Molecule: hsa-mir-130b [309]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/beta-catenin pathway.

Key Molecule: hsa-miR-630 [310]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: CL1-0 cells; Lung; Homo sapiens (Human); CVCL_3871
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: TL4 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Patients with tumors expressing low miR-630, high Bcl-2, and a combination of both were more likely than their counterparts to show unfavorable responses to cisplatin-based chemotherapy.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [311]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; TUNEL assay
• Mechanism Description: LncRNA-MALAT1 contributes to the cisplatin-resistance of lung cancer by upregulating MRP1 and MDR1 via STAT3 activation.

Key Molecule: hsa-mir-181 [312]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-181 downregulation promoted cell growth and metastasis and inhibited cell apoptosis and suppressed LC3 and ATG5 protein expression in A549/DDP cells through suppression of the PTEN/PI3k/AkT/mTOR pathway, whereas miR-181 overexpression recovered LC3 and ATG5 protein expression by promoting PTEN/PI3k/AkT/mTOR signaling.

Key Molecule: hsa-mir-503 [313], [314]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-503 plays a role in the development of drug resistance (Cisplatin) in human non-small cell lung cancer cells, at least in part by targeting the anti-apoptotic protein, Bcl-2.

Key Molecule: hsa-mir-21 [16], [315]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: PTEN signaling pathway; Inhibition; hsa05235
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 decreased the expression of PTEN and increased Bcl-2 in A549. Upregulation of miR-21 induces cholangiocarcinoma cell survival and gemcitabine resistance primarily through targeting the PTEN dependent PI3k/Akt pathway. Inhibition of miR-21 was shown to increase the sensitivity to topotecan in breast cancer cells partly by regulating BCL2 induced anti-apoptosis indirectly in MCF-7 cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [273]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TGF-beta/Smad2/STAT3/STAT5 signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-10a had an important role in promoting drug resistance in tumors through enhancing drug efflux and inhibiting apoptosis via upregulation of MDR1, MRP1 and RhoE expression. In addition, miR-10a promoted the expression of TGF-beta as wells as regulated the activity of the Smad2/STAT3/STAT5 pathway and its downstream transcriptional factors of HIF and eIF4E, which may be the potential mechanism of drug resistance in A549 cells. Therefore, miR-10a may be an important drug target for improving cancer treatment; however, further studies are required to explore the clinical applications of miR-10a inhibitors.

Key Molecule: ATP-binding cassette sub-family A1 (ABCA1) [274]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 106a expression levels were upregulated in the DDP-resistant cell line A549/DDP compared with its parental cell line, A549. miR 106a-transfection induced DDP resistance in A549 cells, while repression of miR 106a by anti miR 106a in A549/DDP resulted in (+) DDP cytotoxicity. Furthermore, it was discovered that the mechanism of miR 106a induced DDP resistance involved the expression of adenosine triphosphatase binding cassette, sub family A, member 1 (ABCA1), as indicated by transfection of cells with short interfering RNA-ABCA1.

Key Molecule: ABC-type oligopeptide transporter ABCB9 (ABCB9) [281]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: LTEP-a-2 cells; Lung; Homo sapiens (Human); CVCL_6929
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-31 is inversely correlated with ABCB9 expression in NSCLC cells. ABCB9 is a direct target of miR-31. Ectopic expression of miR-31 confers DDP-induced apoptosis. Inhibition of ABCB9 is required for DDP resistance.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [311]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; TUNEL assay
• Mechanism Description: LncRNA-MALAT1 contributes to the cisplatin-resistance of lung cancer by upregulating MRP1 and MDR1 via STAT3 activation.

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [316]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ABCC2 knockdown reversed DDP resistance and promoted G1 phase arrest in A549/DDP cells, and PARP and caspase-3 were activated in A549/DDP cells following ABCC2 knockdown. In vivo, ABCC2 knockdown enhanced the cytotoxicity of DDP to subcutaneous A549 t.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [268], [273]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: TGF-beta/Smad2/STAT3/STAT5 signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Vi-cell cell viability analyzer assay; MTS assay; Flow cytometry assay
• Mechanism Description: miR-21 achieves the drug resistance effect through three mechanisms: Increasing MDR1 and MPR1 expression levels, and enhancing drug efflux from the cells; increasing GSH, superoxide dismutase and GST-Pi expression levels and promoting drug inactivation; and inhibiting the PI3k signaling pathway and in turn inhibiting apoptotic signaling. And miR-10a had an important role in promoting drug resistance in tumors through enhancing drug efflux and inhibiting apoptosis via upregulation of MDR1, MRP1 and RhoE expression. In addition, miR-10a promoted the expression of TGF-beta as wells as regulated the activity of the Smad2/STAT3/STAT5 pathway and its downstream transcriptional factors of HIF and eIF4E, which may be the potential mechanism of drug resistance in A549 cells. Therefore, miR-10a may be an important drug target for improving cancer treatment; however, further studies are required to explore the clinical applications of miR-10a inhibitors.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-17 [317]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8-8 assay; Transwell migration assay; Promega assay
• Mechanism Description: miR-17, 20a, 20b were down-regulation in cisplatin-resistant A549/DDP cells compared with A549 cells. inhibition of miR-17, 20a, 20b increased cisplatin-resistant and migration of A549 cells, and over-expression of miR-17, 20a, 20b decreased cisplatin-resistant and migration of A549/DDP cells. miR-17, 20a, 20b blunted the TGFbeta signal pathway by directly inhibiting its important component TGFbetaR2. TGFbetaR2 silenced led to cisplatin sensitivity and migration inhibition in A549/DDP cells.

Key Molecule: hsa-mir-20a [317]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8-8 assay; Transwell migration assay; Promega assay
• Mechanism Description: miR-17, 20a, 20b were down-regulation in cisplatin-resistant A549/DDP cells compared with A549 cells. inhibition of miR-17, 20a, 20b increased cisplatin-resistant and migration of A549 cells, and over-expression of miR-17, 20a, 20b decreased cisplatin-resistant and migration of A549/DDP cells. miR-17, 20a, 20b blunted the TGFbeta signal pathway by directly inhibiting its important component TGFbetaR2. TGFbetaR2 silenced led to cisplatin sensitivity and migration inhibition in A549/DDP cells.

Key Molecule: hsa-mir-20b [317]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8-8 assay; Transwell migration assay; Promega assay
• Mechanism Description: miR-17, 20a, 20b were down-regulation in cisplatin-resistant A549/DDP cells compared with A549 cells. inhibition of miR-17, 20a, 20b increased cisplatin-resistant and migration of A549 cells, and over-expression of miR-17, 20a, 20b decreased cisplatin-resistant and migration of A549/DDP cells. miR-17, 20a, 20b blunted the TGFbeta signal pathway by directly inhibiting its important component TGFbetaR2. TGFbetaR2 silenced led to cisplatin sensitivity and migration inhibition in A549/DDP cells.

Key Molecule: TGF-beta receptor type II (TGFBR2) [317]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8-8 assay; Transwell migration assay; Promega assay
• Mechanism Description: miR-17, 20a, 20b were down-regulation in cisplatin-resistant A549/DDP cells compared with A549 cells. inhibition of miR-17, 20a, 20b increased cisplatin-resistant and migration of A549 cells, and over-expression of miR-17, 20a, 20b decreased cisplatin-resistant and migration of A549/DDP cells. miR-17, 20a, 20b blunted the TGFbeta signal pathway by directly inhibiting its important component TGFbetaR2. TGFbetaR2 silenced led to cisplatin sensitivity and migration inhibition in A549/DDP cells.

Key Molecule: HOXA distal transcript antisense RNA (HOTTIP) [291]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTTIP acts as sponge of miR216a and enhanced the expression of its another target gene, anti-apoptotic gene BCL-2.

Key Molecule: hsa-miR-100-5p [318]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR100-5p-dependent manner, and mTOR acts as a target gene of miR100-5p.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [318]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR100-5p-dependent manner, and mTOR acts as a target gene of miR100-5p.

Key Molecule: hsa-mir-495 [319]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: H69/AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Cell scratch-wound healing assay; Flow cytometry assay
• Mechanism Description: miR495 promotes the chemoresistance of SCLC through the epithelial-mesenchymal transition via Etk/BMX. Ectopic expression of Etk/BMX obviously rescued the miR495 elevation elevation-induced inhibition of drug resistance.

Key Molecule: Ephrin type-A receptor 3 (EPHA3) [319]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: H69/AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical staining; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Cell scratch-wound healing assay; Flow cytometry assay
• Mechanism Description: miR495 promotes the chemoresistance of SCLC through the epithelial-mesenchymal transition via Etk/BMX. Ectopic expression of Etk/BMX obviously rescued the miR495 elevation elevation-induced inhibition of drug resistance.

Key Molecule: Cytoplasmic tyrosine-protein kinase BMX (BMX) [319]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: H69/AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical staining; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Cell scratch-wound healing assay; Flow cytometry assay
• Mechanism Description: miR495 promotes the chemoresistance of SCLC through the epithelial-mesenchymal transition via Etk/BMX. Ectopic expression of Etk/BMX obviously rescued the miR495 elevation elevation-induced inhibition of drug resistance.

Key Molecule: hsa-miR-454-3p [320]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via upregulating Stat3 by sequestering miR-454-3p.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [320]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via upregulating Stat3 by sequestering miR-454-3p.

Key Molecule: HOXA11 antisense RNA (HOXA11-AS) [320]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via upregulating Stat3 by sequestering miR-454-3p.

Key Molecule: ATPase H+ transporting V0 subunit d1 (ATP6V0D1) [321]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Non-small cell lung cancer isolates; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Immunofluorescence assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The drug resistance of cancer cells is likely to be related to the changes in pH gradient between the extracellular environment and the cytoplasm.Vacuolar-H+ -ATPase(V-ATPase) plays a major role in the regulation of cellular pH conditions.The expression of V-ATPase was shown to be related to the pathological type and grade of the cancer and might be associated with the chemotherapy drug resistance in NSCLC.

Key Molecule: ATPase H+ transporting V0 subunit d1 (ATP6V0D1) [321]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Non-small cell lung cancer isolates; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Immunofluorescence assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The drug resistance of cancer cells is likely to be related to the changes in pH gradient between the extracellular environment and the cytoplasm.Vacuolar-H+ -ATPase(V-ATPase) plays a major role in the regulation of cellular pH conditions.The expression of V-ATPase was shown to be related to the pathological type and grade of the cancer and might be associated with the chemotherapy drug resistance in NSCLC.

Key Molecule: ATPase H+ transporting V0 subunit d1 (ATP6V0D1) [321]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Non-small cell lung cancer isolates; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Immunofluorescence assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The drug resistance of cancer cells is likely to be related to the changes in pH gradient between the extracellular environment and the cytoplasm.Vacuolar-H+ -ATPase(V-ATPase) plays a major role in the regulation of cellular pH conditions.The expression of V-ATPase was shown to be related to the pathological type and grade of the cancer and might be associated with the chemotherapy drug resistance in NSCLC.

Key Molecule: Tyrosine kinase with immunoglobulin like and EGF like domains 1 (TIE1) [322]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vivo Model: BALB/c male nude mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; qRT-PCR
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs).

Key Molecule: Tyrosine kinase with immunoglobulin like and EGF like domains 1 (TIE1) [322]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vivo Model: BALB/c male nude mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; qRT-PCR
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [269]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR451/Mcl1/DPP signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DPP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT and cytotoxicity (IC50) assays
• Mechanism Description: miR451 enhanced DPP chemosensitivity of lung cancer cells by negatively regulating Mcl-1 in vitro and in vivo.

Key Molecule: Catenin beta-1 (CTNNB1) [272]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway.The present study detected that the expression levels of Meg3 were significantly lower in cisplatin-resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. The results of the present study also demonstrated that the Meg3-mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, beta-catenin and survivin, which is a target gene of the WNT/beta-catenin signaling pathway.

Key Molecule: Rho-related GTP-binding protein RhoE (RND3) [273]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TGF-beta/Smad2/STAT3/STAT5 signaling pathway; Activation; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-10a had an important role in promoting drug resistance in tumors through enhancing drug efflux and inhibiting apoptosis via upregulation of MDR1, MRP1 and RhoE expression. In addition, miR-10a promoted the expression of TGF-beta as wells as regulated the activity of the Smad2/STAT3/STAT5 pathway and its downstream transcriptional factors of HIF and eIF4E, which may be the potential mechanism of drug resistance in A549 cells. Therefore, miR-10a may be an important drug target for improving cancer treatment; however, further studies are required to explore the clinical applications of miR-10a inhibitors.

Key Molecule: Cation-independent mannose-6-phosphate receptor (IGF2R) [268]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Vi-cell cell viability analyzer assay
• Mechanism Description: miR-21 achieves the drug resistance effect through three mechanisms: Increasing MDR1 and MPR1 expression levels, and enhancing drug efflux from the cells; increasing GSH, superoxide dismutase and GST-Pi expression levels and promoting drug inactivation; and inhibiting the PI3k signaling pathway and in turn inhibiting apoptotic signaling.

Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [276]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p21; Regulation
• Cell Pathway Regulation: p21; Regulation
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-224 could promote the in vitro and in vivo DDP resistance of LA cells via regulating G1/S cell cycle transition and apoptosis. p21WAF1/CIP1, a potent cyclin-dependent kinase inhibitor, was identified as the direct and functional target gene of miR-224. Overexpression of p21WAF1/CIP1 could phenocopy the effect of miR-224 downregulation and silencing of p21WAF1/CIP1 could partially reverse the effect of miR-224 downregulation on DDP resistance of DDP-resistant LA cells. In addition, miR-224 could affect the G1/S transition of cell cycle and apoptosis in LA cells through the p21WAF1/CIP1-pRb pathway and the intrinsic mitochondrial death pathway. Furthermore, miR-224 was found to be downregulated in DDP-responding LA tissues, and its expression was inversely correlated with p21WAF1/CIP1. Multivariate analyses indicated that the status of miR-224 might be an independent prognostic factor for predicting the survival of LA patients.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [277]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-192 induced Cisplatin-resistance and inhibited cell apoptosis in lung cancer via negative targeting Bim expression.

Key Molecule: Homeobox protein Hox-A1 (HOXA1) [278]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: NCI-H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of HOXA1 in immortalised human mammary epithelial cells results in oncogenic transformation and tumour formation in vivo. HOXA1 expression was inversely correlated with miR-100. HOXA1-mediated SCLC chemoresistance is under the regulation of miR-100. HOXA1 may be a prognostic predictor and potential therapeutic target in human SCLC.

Key Molecule: Fanconi anemia group A protein (FANCA) [314]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• Experiment for Molecule Alteration: Luciferase activity assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: FANCA is a candidate target of miR-503, up-regulation of FANCA was inversely associated with the downregulation of miR-503 in NSCLC tissues, Transfection of miR-503 resulted in down-regulation of FANCA. miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin at least in part by targeting FANCA.

Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [280]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression.

Key Molecule: Ribonuclease P protein subunit p21 (RPP21) [280]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression.

Key Molecule: Catenin beta-1 (CTNNB1) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of beta-catenin not only plays a role in the NSCLC tumorigenesis but also increases chemoresistance. NkD2 inhibits beta-catenin by binding to Dvl protein. knockdown Ak126698 in A549 will decreased expression of NkD2, increased expression of whole beta-catenin and nuclear translocation of beta-catenin.

Key Molecule: Protein naked cuticle homolog 2 (NKD2) [283]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of beta-catenin not only plays a role in the NSCLC tumorigenesis but also increases chemoresistance. NkD2 inhibits beta-catenin by binding to Dvl protein. knockdown Ak126698 in A549 will decreased expression of NkD2, increased expression of whole beta-catenin and nuclear translocation of beta-catenin.

Key Molecule: TP53 target 1 (TP53TG1) [283]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA Ak123263, CES1P1-001, RP3-508I15.14, Ak126698, TP53TG1, and AC090952.4.1 decreased, whereas uc003bgl.1 and NCRNA00210 increased in CDDP resistance A549 cell line.

Key Molecule: Phosphatase and tensin homolog (PTEN) [315]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: PTEN signaling pathway; Inhibition; hsa05235
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: PTEN, a tumor suppressor gene, is an essential regulator of cell proliferation, differentiation, growth, and apoptosis. miR-21 can promote growth, migration, and invasion, chemo- or radioresistance of NSCLC cells by downregulation PTEN.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 decreased the expression of PTEN and increased Bcl-2 in A549. Upregulation of miR-21 induces cholangiocarcinoma cell survival and gemcitabine resistance primarily through targeting the PTEN dependent PI3k/Akt pathway. Inhibition of miR-21 was shown to increase the sensitivity to topotecan in breast cancer cells partly by regulating BCL2 induced anti-apoptosis indirectly in MCF-7 cells.

Key Molecule: Protein LYRIC (MTDH) [284]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 clone 23 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1299 clone 41 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The expression of the transcriptional repressor E2F5, a target of miR-128-2, strongly decreases after miR-128-2 exogenous expression. This leads to the abrogation of E2F5 repressive activity on p21waf1 promoter and, consequently, to the transcriptional induction of p21waf1. The newly synthesized p21waf1 protein is mainly localized into the cytoplasmic compartment, where it exerts an anti-apoptotic function in response to anticancer drug treatments.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [36]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [36]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Fas/FasL signaling pathway; Regulation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The anti-apoptotic protein BCL2 and XIAP were upregulated, while the miR-200bc/429 cluster was downregulated in both SGC7901/VCR and A549/CDDP cells. miR-200bc/429 cluster might play an important role in the development of MDR in human gastric and lung cancer cell lines by targeting the anti-apoptotic genes BCL2 and XIAP.

Key Molecule: Dihydropyrimidine dehydrogenase [NADP(+)] [39]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: PC-10 cells; Lung; Homo sapiens (Human); CVCL_7088
• In Vitro Model: QG56 cells; Lung; Homo sapiens (Human); CVCL_6943
• In Vitro Model: RERF-LCMS cells; Lung; Homo sapiens (Human); CVCL_1655
• In Vitro Model: ACC-LC-176 cells; Lung; Homo sapiens (Human); CVCL_7008
• In Vitro Model: RERF-LC-MT cells; Lung; Homo sapiens (Human); CVCL_A473
• In Vitro Model: RERF-LC-Ok cell; Lung; Homo sapiens (Human); CVCL_3154
• In Vitro Model: Sk-LC-10 cells; Lung; Homo sapiens (Human); CVCL_5459
• In Vitro Model: Sk-LC-6 cells; Lung; Homo sapiens (Human); CVCL_5474
• In Vitro Model: VMRC-LCD cells; Lung; Homo sapiens (Human); CVCL_1787
• In Vitro Model: VMRC-LCF cells; Lung; Homo sapiens (Human); CVCL_S848
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Degradation of 5-FU due to DPD is an important determinant in 5-FU sensitivity, while induction of TS contributes to acquired resistance against 5-FU in lung cancer.

Key Molecule: Thymidylate synthase (TYMS) [39]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: PC-10 cells; Lung; Homo sapiens (Human); CVCL_7088
• In Vitro Model: QG56 cells; Lung; Homo sapiens (Human); CVCL_6943
• In Vitro Model: RERF-LCMS cells; Lung; Homo sapiens (Human); CVCL_1655
• In Vitro Model: ACC-LC-176 cells; Lung; Homo sapiens (Human); CVCL_7008
• In Vitro Model: RERF-LC-MT cells; Lung; Homo sapiens (Human); CVCL_A473
• In Vitro Model: RERF-LC-Ok cell; Lung; Homo sapiens (Human); CVCL_3154
• In Vitro Model: Sk-LC-10 cells; Lung; Homo sapiens (Human); CVCL_5459
• In Vitro Model: Sk-LC-6 cells; Lung; Homo sapiens (Human); CVCL_5474
• In Vitro Model: VMRC-LCD cells; Lung; Homo sapiens (Human); CVCL_1787
• In Vitro Model: VMRC-LCF cells; Lung; Homo sapiens (Human); CVCL_S848
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Degradation of 5-FU due to DPD is an important determinant in 5-FU sensitivity, while induction of TS contributes to acquired resistance against 5-FU in lung cancer.

Key Molecule: TGF-beta receptor type II (TGFBR2) [286]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: LncRNA MBNL1-AS1 restoration could decelerate the occurrence and progression of NSCLC, thereby highlighting the functionality of LncRNA MBNL1-AS1 restoration as a sponge of miR-301b-3p to suppress the proliferation, invasion, drug resistance, and sphere formation of CSC cells in NSCLC via upregulation of TGFBR2.

Key Molecule: Phosphatase and tensin homolog (PTEN) [287]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Deregulation of LncRNA-AC078883.3 and microRNA-19a is involved in the development of chemoresistance to cisplatin via modulating signaling pathway of PTEN/AkT.

Key Molecule: Catenin delta-1 (CTNND1) [288]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: MALAT1 could alter chemo-resistance (Cisplatin, Adriamycin, Gefitinib and Paclitaxel) of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.

Key Molecule: H3 lysine 27 trimethylation (H3K27) [289]

• Molecule Alteration: Methylation; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: H3kH3k27me3 induces multidrug resistance in small cell lung cancer by affecting HOXA1 DNA methylation via regulation of the LncRNA HOTAIR.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [37]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: miR17/ATG7 signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA BLACAT1 Can enhance ATG7 expression by suppressing miR-17 expression to promote autophagy and cisplatin resistance in non small cell lung cancer through the miR-17/ATG7 signaling pathway.

Key Molecule: Homeobox protein Hox-A13 (HOXA13) [291]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTTIP acts at least partly by controlling HOXA13 in SCLC poor prognostic and chemoresistance progression.

Key Molecule: Ras-related protein Rab-6A (RAP6A) [292]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter activity assay
• Experiment for Drug Resistance: CD44/CD133 assay; MTT assay
• Mechanism Description: miR5100 increases the cisplatin resistance of the lung cancer stem cells by inhibiting the Rab6. miR5100 increases cisplatin resistance via the mitochondrial apoptosis pathway.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [266]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of LncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. LncRNA-XIST inhibits the expression of miR17 to modulate ATG7 and LncRNA-XIST regulates autophagy through ATG7.

Key Molecule: Transcription factor SOX-4 (SOX4) [294]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: DDP-resistant NSCLC A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA CCAT1/miR130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. CCAT1 effectively acted as a miRNA sponge for miR130a-3p to enhance SOX4 expression.

Key Molecule: Transcription factor SOX-4 (SOX4) [294]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• In Vitro Model: DDP-resistant NSCLC A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA CCAT1/miR130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4. CCAT1 effectively acted as a miRNA sponge for miR130a-3p to enhance SOX4 expression.

Key Molecule: BAG family molecular chaperone regulator 1 (BAG1) [295]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Flow cytometric analysis; TUNEL assay; MTT assay; Colony formation assay
• Mechanism Description: LncRNA XIST overexpression in A549 cells increased their chemosensitivity to cisplatin both in vitro and in vivo by protecting cells from apoptosis and promoting cell proliferation. The function of LncRNA XIST in LAD cells is partially exerted via competitive sponging of let-7i, preventing the inhibition of BAG-1.

Key Molecule: Wnt inhibitory factor 1 (WIF1) [296]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: H1299/DDP cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR181c contributed to DDP resistance in NSCLC cells through activation of the Wnt/beta-catenin pathway by targeting WIF1. miR181c egatively regulates the expression of WIF1, anti-miR181c suppressed the Wnt/beta-catenin pathway by regulating WIF1.

Key Molecule: Polycystin-2 (PKD2) [297]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay; Immunohistochemistry assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR106b-5p enhanced the sensitivity of A549/DDP cells to cisplatin by targeting the expression of PkD2.

Key Molecule: Phosphatase and tensin homolog (PTEN) [298]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Regulation; hsa04151
• Cell Pathway Regulation: miR21/PTEN signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay; RNA immunoprecipitation assay
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: miR21 acts as an oncogenic miRNA through targeting PTEN in many cancers. By negatively regulating the intracellular levels of PI3k, PTEN exerts a suppressive effect on tumor through AkT pathway. miR21 was involved in GAS5 regulation of NSCLC sensitivity to DDP through PTEN pathway.

Key Molecule: Phosphatase and tensin homolog (PTEN) [298]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay; RNA immunoprecipitation assay
• Experiment for Drug Resistance: MTT assay; Soft agar assay
• Mechanism Description: GAS5 could compete with PTEN for miR21 binding, GAS5 downregulation can induce trastuzumab resistance of breast cancer By negatively regulating the intracellular levels of PI3k, PTEN exerts a suppressive effect on tumor through AkT pathway. GAS5 regulated NSCLC chemo-sensitivity to DDP-based therapy through PTEN pathway.

Key Molecule: Ubiquitin-like protein ATG12 (ATG12) [299]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR146a-5p increases chemosensitivity of NSCLC to cisplatin by targeting Atg12 to inhibit autophagy.

Key Molecule: Eukaryotic translation initiation factor 3 subunit A (EIF3A) [300]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NER signaling pathway; Activation; hsa03420
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Cell Titer 96 AQueous One Solution Assay; Annexin V FITC Apoptosis assay; Clone formation assay
• Mechanism Description: miRNA-488 inhibited eIF3a expression by directly binding to the 3'UTR of eIF3a, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC).

Key Molecule: Translationally-controlled tumor protein (TCTP) [302]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: pim-3 signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulation of miR-1236-3p could reverse DDP resistance in lung cancer cells through targeting TPT1 and inhibition of the Pim-3 signaling pathway.

Key Molecule: NFE2-related factor 2 (NRF2) [303]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-144-3p promotes cisplatin sensitivity by downregulating Nrf2 in lung cancer cells.

Key Molecule: DNA damage-inducible transcript 3 (DDIT3) [308]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA 146a promotes chemotherapy resistance in lung cancer cells by targeting DNA damage inducible transcript 3 (CHOP).

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [310]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: CL1-0 cells; Lung; Homo sapiens (Human); CVCL_3871
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: TL4 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Patients with tumors expressing low miR-630, high Bcl-2, and a combination of both were more likely than their counterparts to show unfavorable responses to cisplatin-based chemotherapy.

Key Molecule: Phosphatase and tensin homolog (PTEN) [312]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-181 downregulation promoted cell growth and metastasis and inhibited cell apoptosis and suppressed LC3 and ATG5 protein expression in A549/DDP cells through suppression of the PTEN/PI3k/AkT/mTOR pathway, whereas miR-181 overexpression recovered LC3 and ATG5 protein expression by promoting PTEN/PI3k/AkT/mTOR signaling.

Key Molecule: Phosphatase and tensin homolog (PTEN) [305], [307], [309]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell survival; Inhibition; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; SA-beta-gal assay
• Mechanism Description: Suppression of miR-221 could lead to increase of PTEN expression level and enhance the CDDP chemosensitivity. And miRNA 328 overexpression confers cisplatin resistance in non small cell lung cancer via targeting of PTEN. And microRNA-130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/beta-catenin pathway.

Key Molecule: Programmed cell death protein 4 (PDCD4) [275], [270]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay and TUNEL assay
• Mechanism Description: The expression level of miR-182 in A549 cell line was significantly higher than that in NHBE cell line. Transfection of miR-182 inhibitor induced sensitivity of A549 cells to cisplatin. A549 cells transfected with PDCD4 siRNA became more resistant to cisplatin therapy. We found an increase PDCD4 protein level following the transfection of miR-182 inhibitor using Western blot analysis. In addition, the (+) growth-inhibitory effect by miR-182 inhibitor was weakened after the addition of PDCD4 siRNA. And miR-141 expression was significantly up-regulated in cisplatin-resistant A549/DDP cells compared with the parental cell line A549; and PDCD4, an important apoptosis regulator, was found to be down-regulated. Luciferase activity assay and Western blot analysis confirmed that PDCD4 is a direct target of miR-141. Inhibition of miR-141 in A549/DDP cells markedly increased cisplatin sensitivity and apoptosis, which was partially abrogated by PDCD4 inhibition, indicating that PDCD4 is a functional target of miR-141 in of the regulation of cisplatin sensitivity.

Key Molecule: Phosphatase and tensin homolog (PTEN) [16], [282]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN signaling pathway; Regulation; hsa05235
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-205 promotes the growth of the NSCLC cell lines, miR-205 is inversely correlated with PTEN expression, miR-205 has the ability to promote growth, migration, invasion and chemoresistance of NSCLC cells by targeting PTEN. And miR-21 decreased the expression of PTEN and increased Bcl-2 in A549. Upregulation of miR-21 induces cholangiocarcinoma cell survival and gemcitabine resistance primarily through targeting the PTEN dependent PI3k/Akt pathway. Inhibition of miR-21 was shown to increase the sensitivity to topotecan in breast cancer cells partly by regulating BCL2 induced anti-apoptosis indirectly in MCF-7 cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [323]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549/DPP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299/DDP cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis; Luciferase reporter assay; Dual-luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR133b reduces cisplatin resistance and its overexpression contributes to the suppression of the malignant growth and aggressiveness of cisplatin-resistant NSCLC cells by targeting GSTP1.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-185-5p [324]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay
• Mechanism Description: miR185-5p exhibited negative correlation with ABCC1 in A549/DDP cells., inhibition of miR185-5p was involved in chemo-resistance of NSCLC cells to cisplatin via down-regulating ABCC1.

Key Molecule: hsa-mir-335 [325]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H446/DDP cells; Lung; Homo sapiens (Human); CVCL_RT21
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-PE Apoptosis assay; Flow cytometry assay; Wound healing assay; Colony formation assay
• Mechanism Description: miR335 might affect the chemosensitivity and radiosensitivity of SCLC by targeting PARP-1, which further affected NF-kB P65 protein levels, hence NF-kB pathway was involved in the regulation network.

Key Molecule: hsa-mir-34 [326]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR34a sensitizes lung cancer cells to cisplatin via p53/miR34a/MYCN axis, miR34a directly targeted to MYCN to sensitize NSCLC cells to cisplatin.

Key Molecule: hsa-mir-135b [327]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC and PI apoptosis detection assay
• Mechanism Description: miR135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1.

Key Molecule: hsa-miR-33b-3p [328]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NER signaling pathway; Regulation; hsa03421
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Alamar blue assay; EdU cell proliferation assay
• Mechanism Description: miR-33-3b-3p exerted a critical role in modulating the cisplatin sensitivity of lung cancer cells, which might probably through suppressing the p21 expression.

Key Molecule: hsa-miR-30c-2-3p [329]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: TL-1 cells; Lung; Homo sapiens (Human); CVCL_B371
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Immunohistochemical staining assay
• Mechanism Description: miR-30c-2* negative regulated MTA-1 expression involved in metastasis and reducing drug resistance of HPV-infected non-small cell lung cancer.

Key Molecule: Metastasis-associated protein MTA1 (MTA1) [329]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: TL-1 cells; Lung; Homo sapiens (Human); CVCL_B371
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Immunohistochemical staining assay
• Mechanism Description: miR-30c-2* negative regulated MTA-1 expression involved in metastasis and reducing drug resistance of HPV-infected non-small cell lung cancer.

Key Molecule: hsa-miR-98-5p [330]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Ubiquitin-proteasome signaling pathway; Regulation; hsa05017
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: NEAT1 may act as a competing endogenous LncRNA to upregulate EGCG-induced CTR1 by sponging hsa-mir-98-5p to upregulates EGCG-induced CTR1 to enhance cisplatin sensitivity in lung cancer cells.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [330]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Ubiquitin-proteasome signaling pathway; Regulation; hsa05017
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: NEAT1 may act as a competing endogenous LncRNA to upregulate EGCG-induced CTR1 by sponging hsa-mir-98-5p to upregulates EGCG-induced CTR1 to enhance cisplatin sensitivity in lung cancer cells.

Key Molecule: hsa-miR-206 [331]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MET/PI3K/AKT/mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-206 overexpression in human lung adenocarcinoma cisplatin resistant cells inhibited the EMT and cisplatin resistance by targeting MET and suppressing its downstream PI3k/AkT/mTOR signaling pathway. Low expression of miR-206 and high levels of MET were strongly associated with the poor cisplatin sensitivity of lung adenocarcinoma patients. Therefore, activation of miR-206 or inactivation of its target gene pathway may be a potential strategy to reverse cisplatin resistance in human lung adenocarcinoma cisplatin resistant cells.

Key Molecule: hsa-mir-137 [332]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/PTX cells; Lung; Homo sapiens (Human); CVCL_W218
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-137 in A549/PTX and A549/CDDP cells inhibited cell proliferation, migration, induced cell apoptosis, arrest the cell cycle in G1 phase and reversed drug resistance to PTX and CDDP in A549/PTX and A549/CDDP cell lines respectively. NUCkS1 is a direct target of miR-137, and is elevated in human lung cancer tissues, which is inversely correlated with miR-137 expression levels. miR-137 enhances the chemosensitivity of paclitaxel and cisplatin in vivo.

Key Molecule: hsa-mir-196a [333]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-196a was upregulated in human NSCLC tissues and cell lines; the downregulation of miR-196a (+) the sensitivity of NSCLC cell lines (SPC-A-1, A549) to DDP through the induction of apoptosis by targeting homeobox A5 (HOXA5). Taken together, these findings suggest that miR-196a is a valid therapeutic target with the potential to be employed as a novel multimodality therapy as part of a strategy for the treatment of patients with NSCLC.

Key Molecule: hsa-mir-194 [334]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• In Vitro Model: 95C cells; Lung; Homo sapiens (Human); CVCL_7109
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic stable expression miR-194 suppressed proliferation, migration, invasion and metastasis and induced apoptosis in NSCLC cells and that this suppression could be reversed by reintroducing forkhead box A1 (FOXA1), a functional target of miR-194. In addition, miR-194 was downregulated in in cisplatin-resisted human NSCLC cell line-A549/DDP and overexpression of miR-194 increases cisplatin sensitivity.

Key Molecule: hsa-mir-378 [335]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Anip973 cells; Lung; Homo sapiens (Human); CVCL_6879
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Altered expression of miR-378 in human lung adenocarcinoma cell lines with varying sensitivities to cDDP, and have shown that miR-378 can restore cDDP chemosensitivity in the human lung adenocarcinoma cells by targeting sCLU and downregulating Bcl-2, pCas-3, pErk1/2 and pAkt.

Key Molecule: hsa-mir-181 [336]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-BetaR1/Smad signaling pathway; Inhibition; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181b inhibited cell proliferation, augmented the chemosensitivity to DDP, suppressed migration and invasion in NSCLC cells miR-181b inhibited cell proliferation, augmented the chemosensitivity to DDP, suppressed migration and invasion in NSCLC cells in vitro and in vivo. Furthermore, miR-181b may increase chemosensitivity to DDP and suppress the invasion and metastasis of NSCLC cells through directly targeting the TGFbetaR1 signaling miR-181b may increase chemosensitivity to DDP and suppress the invasion and metastasis of NSCLC cells through directly targeting the TGFbetaR1 signaling pathway.

Key Molecule: hsa-mir-26a [337]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: HMGA2-E2F1-AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Decreased MicroRNA-26a expression significantly decreased the expression of E2F1, diminished Akt phosphorylation, and downregulated Bcl2 expression, which causes cisplatin resistance in human non-small cell lung cancer.

Key Molecule: Maternally expressed 3 (MEG3) [272]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway.The present study detected that the expression levels of Meg3 were significantly lower in cisplatin-resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. The results of the present study also demonstrated that the Meg3-mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, beta-catenin and survivin, which is a target gene of the WNT/beta-catenin signaling pathway.

Key Molecule: hsa-mir-148b [338]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The data showed a down-regulated of miR-148b expression and evaluated methyltransferases (DNMTs) expression in cisplatin-resisted human non-small cell lung cancer (NSCLC) cell line-A549/DDP and SPC-A1/DDP compared with their parental A549 and SPC-A1 cell line. In transfection experiments, miR-148b mimics reduced the DNMT1 expression, as well as (+) the sensitivity of cells to cisplatin and cisplatin-induced apoptosis in A549/DDP or SPC-A1/DDP cells. While miR-148b inhibitor increased DNMT1 expression, as well as attenuated the sensitivity of cells to cisplatin in A549 and SPC-A1 cells. miR-148b was showed to exert negative effect on DNMT1 expression by targeting its 3'UTR in A549/DDP and A549 cells. Importantly, silenced DNMT1 increases cisplatin sensitivity of A549/DDP cells and over-expressed DNMT1 reverses pro-apoptosis effect of miR-148b mimic.

Key Molecule: hsa-miR-107 [339]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The A549 cells transfected with miR-107 mimics were significantly more sensitive to the therapy of cisplatin than control cells. A549 cells Transfected with miR-107 mimics showed a decreased CDk8 protein expression. Down-regulation of CDk8 expression by siRNAs, A549 cells became more sensitive to the therapy of cisplatin. In addition, the (+) growth-inhibitory effect by the miR-107 mimic transfection was (+) after the addition of CDk8 siRNA. The present study provides the first evidence that miR-107 plays a key role in cisplatin resistance by targeting the CDk8 protein in NSCLC cell lines, suggesting that miR-107 can be used to predict a patient's response to chemotherapy as well as serve as a novel potential maker for NSCLC therapy.

Key Molecule: hsa-mir-217 [340]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-217 suppresses tumour development in lung cancer by targeting kRAS and enhances cell sensitivity to cisplatin.

Key Molecule: hsa-mir-494 [341]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCL2 signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Knockdown of SCGN led to significantly increasing of chemosensitivity, which is similar to those induced by miR-494 mimics, and ectopic expression of SCGN could rescue the suppressive effect of miR-494.

Key Molecule: hsa-mir-137 [342]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H446/CDDP cells; Lung; Homo sapiens (Human); CVCL_RT21
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-137 was closely related to MDR of SCLC, and interference of miR-137 expression may attenuate drug resistant of H446/CDDP cells to cisplatin, partially through kIT expression regulation. kIT might be only one of the downstream molecules of miR-137 that related to SCLC MDR.

Key Molecule: hsa-mir-503 [343]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Clonogenicity assay
• Mechanism Description: miR-503 was able to reverse the cisplatin resistance of A549/DDP. miR-503 processed this kind of effect by inhibiting the drug efflux, downregulating the expression of drug-resistant related proteins and promoting cell apoptosis.

Key Molecule: Beclin-1 (BECN1) [58]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-30d [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-92b [344]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-92b promotes, while knockdown of it inhabits A549 cell growth, miR-92b regulates the resistance of NSCLC A549 cells to CDDP, Anti-miR-92b sensitizes A549/CDDP cells to CDDP-induced apop-tosis, miR-92b down-regulates PTEN expression at mRNA and protein level in A549 cells, PTEN plays important roles in cell cycle detention and apoptosis, regulation of cell adherence, migration, differentiation and has the function of enhancing the sensitivity of cancer cells to certain anticancer agents.

Key Molecule: hsa-mir-103 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-mir-135a [345]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hsa-miR-135a/b could play a role in the development of CDDP resistance in lung cancer cell line at least in partby modulation of apoptosis via targeting MCL1.

Key Molecule: hsa-mir-135b [345]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hsa-miR-135a/b could play a role in the development of CDDP resistance in lung cancer cell line at least in partby modulation of apoptosis via targeting MCL1.

Key Molecule: hsa-mir-152 [346]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: hsa-mir-34 [347]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SBC5 cells; Lung; Homo sapiens (Human); CVCL_1679
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cells pretreated with siR-Sirt1 are more sensitive to DDP than the control pretreated cells, miR-34a down-regulation Sirt1 and sensitizes lung cancer cell lines to DDP.

Key Molecule: hsa-mir-155 [348]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Apaf-1 is a core molecule in the mitochondrial apoptotic pathway, relaying the death signal to the heptameric apoptosome complex to ignite the downstream cascade of caspases. Down-regulation of miR-155 could enhance the sensitivity of A549 cells to cisplatin treatment via restoration of the Apaf-1 pathway.

Key Molecule: hsa-miR-513a-3p [349]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: GSTP1 augment drug resistance by catalyzing GSH-drug binding, exogenous miR-513a-3p plays a role in sensitizing human lung adenocarcinoma cell lines to cisplatin by repressing GSTP1 expression at the translational level.

Key Molecule: hsa-mir-451 [350]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ectopic overexpression of miR-451 could sensitize A549 cells to DDP possibly by increasing DDP-induced apoptosis which might be associated with the inactivation of Akt signaling pathway.

Key Molecule: hsa-mir-497 [213]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Enforced miR-497 expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, has-miR-497 could play a role in both gastric and lung cancer cell lines at least in part by modulation of apoptosis via targeting BCL2.

Key Molecule: hsa-mir-200c [351]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: Calu1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• Experiment for Molecule Alteration: Methylation-specific PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reintroduction of miR-200c into highly invasive/aggressive NSCLC cells induced a loss of the mesenchymal phenotype by restoring E-cadherin and reducing N-cadherin expression, and inhibited in vitro cell invasion as well as in vivo metastasis formation.

Key Molecule: hsa-mir-181 [214]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Key Molecule: Cancer susceptibility 2 (CASC2) [352]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: ERK1/2 and Beta-catenin signaling pathway; Inhibition; hsa04210
• In Vitro Model: H226 Cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Increasing the CASC2c expression level could reverse the resistance of NSCLC cells to cisplatin.

Key Molecule: hsa-miR-219a-5p [353]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR-219a-5p enhances cisplatin sensitivity of human non-small cell lung cancer by targeting FGF9.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [291]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR216a.

Key Molecule: hsa-mir-381 [354]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR381 suppresses the growth and increases cisplatin sensitivity in non-small cell lung cancer cells through inhibition of nuclear factor-kB signaling. miR381 suppresses the activation of NF-kB signaling by targeting ID1.

Key Molecule: hsa-mir-216b [355]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: c-Jun/BCL-xl signaling pathway; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR216b sensitizes NSCLC cells to cisplatin-induced apoptosis by decreasing the expression of c-Jun and inhibiting the c-Jun/Bcl-xl pathway.

Key Molecule: Surfactant associated 1, LncRNA (SFTA1P) [356]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: A549-DDP cells; Lung; Homo sapiens (Human); CVCL_IP03
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS Cell Proliferation Assay; EdU assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA SFTA1P promoted apoptosis and increased cisplatin chemosensitivity via regulating the hnRNP-U-GADD45A axis in lung squamous cell carcinoma. SFTA1P could up-regulate hnRNP-U expression. hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A.

Key Molecule: X inactive specific transcript (XIST) [266]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: lncRNA-XIST/miR17 axis; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of LncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. LncRNA-XIST inhibits the expression of miR17 to modulate ATG7 and LncRNA-XIST regulates autophagy through ATG7.

Key Molecule: Maternally expressed 3 (MEG3) [357]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Caspase-3 activity analysis
• Mechanism Description: LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR21-5p/SOX7 axis. miR21-5p significantly abolished the effects of MEG3 on DDP resistance via modulating cell proliferation and apoptosis. SOX7 was identified as a direct target of miR21-5p and MEG3 positively regulated SOX7 expression by suppressing miR21-5p.

Key Molecule: hsa-miR-21-5p [357]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; RNA immunoprecipitation (RIP) assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Caspase-3 activity analysis
• Mechanism Description: LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR21-5p/SOX7 axis. miR21-5p significantly abolished the effects of MEG3 on DDP resistance via modulating cell proliferation and apoptosis. SOX7 was identified as a direct target of miR21-5p and MEG3 positively regulated SOX7 expression by suppressing miR21-5p.

Key Molecule: hsa-miR-30a-5p [358]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: Letp cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; WB assay; Colony formation assay; Fow cytometric analysis
• Mechanism Description: Beclin-1-dependent autophagy in SCLC was directly regulated by miR30a-5p. miR30a-5p contributed to chemoresistance of SCLC cells partially in an Beclin-1-dependent manneRNA.

Key Molecule: hsa-let-7i [295]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometric analysis; TUNEL assay; MTT assay; Colony formation assay
• Mechanism Description: LncRNA XIST overexpression in A549 cells increased their chemosensitivity to cisplatin both in vitro and in vivo by protecting cells from apoptosis and promoting cell proliferation. XIST functioned as competing endogenous RNA to repress let-7i, which controlled its down-stream target BAG-1.

Key Molecule: hsa-mir-493 [359]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/NF-kB signaling pathway; Activation; hsa04151
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: Epigenetic silencing of miR493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1). TCRP1 mediated a specific resistance to cDDP part due to activation of the PI3k/Akt/NF-kB signaling pathway.

Key Molecule: TRPM2 antisense RNA (TRPM2-AS) [360]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53/p66shc signaling pathway; Activation; hsa04115
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Downregulated long non-coding RNA TRPM2-AS inhibits cisplatin resistance of non-small cell lung cancer cells via activation of p53- p66shc pathway.

Key Molecule: hsa-miR-129-5p [361]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; DAPI staining assay
• Mechanism Description: miR129-5p inhibits non-small cell lung cancer cell stemness and chemoresistance through targeting DLk1.

Key Molecule: hsa-mir-7 [362]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Upregulation of miR7 increases the sensitivity of LA cells to CDDP via induction of apoptosis by targeting Bcl-2.

Key Molecule: hsa-miR-369-3p [363]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR369-3p/SLC35F5 signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: Attenuation of deregulated miR369-3p expression sensitizes non-small cell lung cancer cells to cisplatin via modulation of the nucleotide sugar transporter SLC35F5.

Key Molecule: hsa-miR-1244 [364]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; LDH assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR1244 suppressed cell viability and increased LDH toxicity in cisplatin-treated A549 and NCI-H522 cells and induced the apoptosis of cisplatin-treated A549 and NCI-H522 cells. Overexpression of miR1244 promoted caspase-3 activity and p53 and Bax protein expression, and suppressed MEF2D and cyclin D1 protein expression in cisplatin treated A549 and NCI-H522 cells.

Key Molecule: hsa-miR-142-3p [365]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Caspase-3 and TUNEL staining assay; MTT assay
• Mechanism Description: miR142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3k/Akt/mTOR pathway. miR142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo.

Key Molecule: hsa-mir-203 [366]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NHBE cells; Lung; Homo sapiens (Human); CVCL_S124
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Caspase 3/7 apoptosis assay
• Mechanism Description: Overexpression of miR203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1.

Key Molecule: piR-l-138 [367]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: NCl-H1792 cells; Lung; Homo sapiens (Human); CVCL_1495
• In Vitro Model: NCl-H1944 cells; Lung; Homo sapiens (Human); CVCL_1508
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: piR-L-138 directly interacted with p60-MDM2 and inhibited CDDP-activated apoptosis in p53-mutated LSCC.

Key Molecule: hsa-mir-146a [368]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1/DDP cells; Kidney; Homo sapiens (Human); CVCL_6955
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Transwell migration assay; Flow cytometric analysis
• Mechanism Description: Up-regulation of miR146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J.

Key Molecule: Eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) [369]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay; Immunoblotting assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: Suppression of EIF4G2 by miR379 potentiates the cisplatin chemosensitivity in nonsmall cell lung cancer cells.

Key Molecule: hsa-mir-379 [369]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: Suppression of EIF4G2 by miR379 potentiates the cisplatin chemosensitivity in nonsmall cell lung cancer cells.

Key Molecule: hsa-mir-29a [370]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: microRNA 29a enhances cisplatin sensitivity in non small cell lung cancer through the downregulation of REV3L.

Key Molecule: hsa-mir-202 [371]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Inhibition; hsa04010
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H441 cells; Lung; Homo sapiens (Human); CVCL_1561
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The overexpression of miR-202 was found to inhibit the Ras/MAPk pathway by targeting the kRas gene.

Key Molecule: hsa-mir-181 [372]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch2/HES1 signaling pathway; Inhibition; hsa04330
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Ectopic miR-181b expression suppressed cancer stem cell properties and enhanced sensitivity to cisplatin (DDP) treatment by directly targeting Notch2.

Key Molecule: hsa-mir-9 [373]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; EdU assay
• Mechanism Description: microRNA-9 Enhanced Cisplatin Sensitivity in Nonsmall Cell Lung Cancer Cells by downregulating Eukaryotic Translation Initiation Factor 5A2.

Key Molecule: NNT antisense RNA 1 (NNT-AS1) [374]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/Slug signaling pathway; Regulation; hsa04010
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA NNT-AS1 is a major mediator of cisplatin chemoresistance in non-small cell lung cancer through MAPk/Slug pathway.

Key Molecule: hsa-mir-1 [375]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-1 enhanced DDP sensitivity of DDP resistant NSCLC cells by downregulating ATG3.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [376]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Si-HOTAIR interference significantly increased the sensitivity of cells to DDP, the IC50 of cells was decreased from 131.85 to 44.34 M (P<0.05), the expression levels of MRP1 and MDR1 were significantly decreased, and the activation of Wnt signaling pathway was significantly inhibited.

Key Molecule: hsa-mir-18a [377]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR18a/PTEN signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TP53TG1 increased the sensitivity of NSCLC cells to cisplatin by modulating miR-18a/PTEN axis by promoting PTEN expression via inhibiting miR-18a.

Key Molecule: TP53 target 1 (TP53TG1) [377]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR18a/PTEN signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TP53TG1 increased the sensitivity of NSCLC cells to cisplatin by modulating miR-18a/PTEN axis by promoting PTEN expression via inhibiting miR-18a.

Key Molecule: hsa-mir-29a [378]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Caspase-3 Activity Assay
• Mechanism Description: miR-29a renders lung cancer cells more sensitive to cisplatin treatment and miR-29a and cisplatin combination promoted apoptotic effect through targeting NRAS in lung cancer cells.

Key Molecule: hsa-miR-133b [379], [323]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549/DPP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299/DDP cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR133b reduces cisplatin resistance and its overexpression contributes to the suppression of the malignant growth and aggressiveness of cisplatin-resistant NSCLC cells by targeting GSTP1.

Key Molecule: hsa-mir-21 [380], [381]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of miR-21 inhibited growth, colony formation, antiapoptotic Bcl-2 expression and promoted proapoptotic Bax and caspase-9 expression in A549 cells treated with DDP. Upregulation of miR-21 promoted growth and colony formation in Sk-MES-1 cells treated with DDP. Furthermore, downregulation of miR-21 reduced growth of implanted tumors, suggesting that miR-21 inhibition could enhance the sensitivity of A549 cells to DDP in vivo. These data suggest an appropriate combination of DDP and miR-21 regulation might be a potential approach to lung cancer therapy. Combined DDP application with miR-21 downregulation for the treatment of lung cancer would help achieve effective treatment and reduce DDP side effects.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [324]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay
• Mechanism Description: miR185-5p exhibited negative correlation with ABCC1 in A549/DDP cells., inhibition of miR185-5p was involved in chemo-resistance of NSCLC cells to cisplatin via down-regulating ABCC1.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [381]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-21 mainly achieves drug resistance by inhibiting cisplatin-induced apoptosis, and its specific mechanisms include the following: (1) improving the expression level of EGFR and protecting the toxic effect of tumor cells during chemotherapy; (2) Increase the expression of LRP and decrease the effective concentration of the target drug through the barrier of drug transport between nucleus and cell; (3) Enhance the expression of multidrug resistance associated protein (MRP1) and assist in pumping chemotherapeutic drugs from the inside to the outside of the cell.

Key Molecule: Solute carrier family 35 member F5 (SLC35F5) [363]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR369-3p/SLC35F5 signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: Attenuation of deregulated miR369-3p expression sensitizes non-small cell lung cancer cells to cisplatin via modulation of the nucleotide sugar transporter SLC35F5.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [376]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Si-HOTAIR interference significantly increased the sensitivity of cells to DDP, the IC50 of cells was decreased from 131.85 to 44.34 M (P<0.05), the expression levels of MRP1 and MDR1 were significantly decreased, and the activation of Wnt signaling pathway was significantly inhibited.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [376]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Si-HOTAIR interference significantly increased the sensitivity of cells to DDP, the IC50 of cells was decreased from 131.85 to 44.34 M (P<0.05), the expression levels of MRP1 and MDR1 were significantly decreased, and the activation of Wnt signaling pathway was significantly inhibited.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-203 [382]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Direct interaction between miR203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance. ZEB2 was found to be a direct target of miR203, which induces epithelial-mesenchymal transition (EMT) signal.

Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2) [382]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Direct interaction between miR203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance. ZEB2 was found to be a direct target of miR203, which induces epithelial-mesenchymal transition (EMT) signal.

Key Molecule: hsa-mir-101 [383]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: NCI-460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Transwell migration assay; MTS assay
• Mechanism Description: Low miR-101 expression promotes EMT in cisplatin-resistant NSCLC cells. ROCk2 was the direct target of miR-101 and that ROCk2 overexpression reversed miR-101-mediatedEMT and cisplatin resistance in NSCLC cells. ROCk2 protein levels were inversely correlated with miR-101 levels in NSCLC tissue samples and that low miR-101 expression was correlated with poor survival time.

Key Molecule: Rho-associated protein kinase 2 (ROCK2) [383]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: NCI-460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Transwell migration assay; MTS assay
• Mechanism Description: Low miR-101 expression promotes EMT in cisplatin-resistant NSCLC cells. ROCk2 was the direct target of miR-101 and that ROCk2 overexpression reversed miR-101-mediatedEMT and cisplatin resistance in NSCLC cells. ROCk2 protein levels were inversely correlated with miR-101 levels in NSCLC tissue samples and that low miR-101 expression was correlated with poor survival time.

Key Molecule: CX3C chemokine receptor 1 (CX3CR1) [384]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: D6 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LAX cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LTEP-2 cells; Lung; Homo sapiens (Human); CVCL_6929
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR296-3p inhibited NSCLC cell proliferation, enhance the drug resistance, and apoptosis. Data of luciferase reporter assays demonstrated that the CX3CR1 gene was a direct regulator of tumorsuppressive miR296-3p. Moreover, overexpressed CX3CR1 was confirmed in NSCLC clinical specimens. Inhibition of CX3CR1 could inhibit cancer cellular survival and increase chemotherapy sensitivity. There was a negative relationship between miR296-3p and CX3CR1 expression in NSCLC tissues.

Key Molecule: hsa-miR-296-3p [384]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: D6 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LAX cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LTEP-2 cells; Lung; Homo sapiens (Human); CVCL_6929
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR296-3p inhibited NSCLC cell proliferation, enhance the drug resistance, and apoptosis. Data of luciferase reporter assays demonstrated that the CX3CR1 gene was a direct regulator of tumorsuppressive miR296-3p. Moreover, overexpressed CX3CR1 was confirmed in NSCLC clinical specimens. Inhibition of CX3CR1 could inhibit cancer cellular survival and increase chemotherapy sensitivity. There was a negative relationship between miR296-3p and CX3CR1 expression in NSCLC tissues.

Key Molecule: hsa-mir-200b [385]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-200b was down-regulated in the resistant cells and enforced expression of miR-200b by miRNA mimics increased cell sensitivity. Overexpression of miR-200b led to the downregulation of ZEB2 at protein level. Luciferase reporter gene assay showed that 3'UTR ZEB2 activity was regulated by miR-200b. ZEB2 modulates drug resistance and is regulated by miR-200b. knockdown of ZEB2 increased cell sensitivity through increasing drug-induced cell apoptosis accompanied with S phase arrest. ZEB2 was regulated by miR-200b at protein level.

Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2) [385]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-200b was down-regulated in the resistant cells and enforced expression of miR-200b by miRNA mimics increased cell sensitivity. Overexpression of miR-200b led to the downregulation of ZEB2 at protein level. Luciferase reporter gene assay showed that 3'UTR ZEB2 activity was regulated by miR-200b. ZEB2 modulates drug resistance and is regulated by miR-200b. knockdown of ZEB2 increased cell sensitivity through increasing drug-induced cell apoptosis accompanied with S phase arrest. ZEB2 was regulated by miR-200b at protein level.

Key Molecule: Cadherin-2 (CDH2) [386]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Abrogation of LncRNA UCA1 reverses drug resistance in A549/DDP cells and inhibits EMT in A549/DDP cells via downregulating N-cadherin.

Key Molecule: Urothelial cancer associated 1 (UCA1) [386]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Abrogation of LncRNA UCA1 reverses drug resistance in A549/DDP cells and inhibits EMT in A549/DDP cells via downregulating N-cadherin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [325]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H446/DDP cells; Lung; Homo sapiens (Human); CVCL_RT21
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-PE Apoptosis assay; Flow cytometry assay; Wound healing assay; Colony formation assay
• Mechanism Description: miR335 might affect the chemosensitivity and radiosensitivity of SCLC by targeting PARP-1, which further affected NF-kB P65 protein levels, hence NF-kB pathway was involved in the regulation network.

Key Molecule: N-myc proto-oncogene protein (MYCN) [326]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: BEAS-2B cells; Bronchus; Homo sapiens (Human); CVCL_0168
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR34a sensitizes lung cancer cells to cisplatin via p53/miR34a/MYCN axis, miR34a directly targeted to MYCN to sensitize NSCLC cells to cisplatin.

Key Molecule: Frizzled-1 (FZD1) [327]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-FITC and PI apoptosis detection assay
• Mechanism Description: miR135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1.

Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [328]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NER signaling pathway; Regulation; hsa03421
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Alamar blue assay; EdU cell proliferation assay
• Mechanism Description: miR-33-3b-3p exerted a critical role in modulating the cisplatin sensitivity of lung cancer cells, which might probably through suppressing the p21 expression.

Key Molecule: Solute carrier family 31 member 1 (SLC31A1) [330]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Ubiquitin-proteasome signaling pathway; Regulation; hsa05017
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: NEAT1 may act as a competing endogenous LncRNA to upregulate EGCG-induced CTR1 by sponging hsa-mir-98-5p to upregulates EGCG-induced CTR1 to enhance cisplatin sensitivity in lung cancer cells.

Key Molecule: Epidermal growth factor receptor (EGFR) [381]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-21 mainly achieves drug resistance by inhibiting cisplatin-induced apoptosis, and its specific mechanisms include the following: (1) improving the expression level of EGFR and protecting the toxic effect of tumor cells during chemotherapy; (2) Increase the expression of LRP and decrease the effective concentration of the target drug through the barrier of drug transport between nucleus and cell; (3) Enhance the expression of multidrug resistance associated protein (MRP1) and assist in pumping chemotherapeutic drugs from the inside to the outside of the cell.

Key Molecule: Lipoprotein receptor-related protein (LRP) [381]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-21 mainly achieves drug resistance by inhibiting cisplatin-induced apoptosis, and its specific mechanisms include the following: (1) improving the expression level of EGFR and protecting the toxic effect of tumor cells during chemotherapy; (2) Increase the expression of LRP and decrease the effective concentration of the target drug through the barrier of drug transport between nucleus and cell; (3) Enhance the expression of multidrug resistance associated protein (MRP1) and assist in pumping chemotherapeutic drugs from the inside to the outside of the cell.

Key Molecule: Hepatocyte growth factor receptor (MET) [331]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MET/PI3K/AKT/mTOR signaling pathway; Regulation; hsa04150
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-206 overexpression in human lung adenocarcinoma cisplatin resistant cells inhibited the EMT and cisplatin resistance by targeting MET and suppressing its downstream PI3k/AkT/mTOR signaling pathway. Low expression of miR-206 and high levels of MET were strongly associated with the poor cisplatin sensitivity of lung adenocarcinoma patients. Therefore, activation of miR-206 or inactivation of its target gene pathway may be a potential strategy to reverse cisplatin resistance in human lung adenocarcinoma cisplatin resistant cells.

Key Molecule: Nuclear ubiquitous casein CDK substrate 1 (NUCKS1) [332]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/PTX cells; Lung; Homo sapiens (Human); CVCL_W218
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-137 in A549/PTX and A549/CDDP cells inhibited cell proliferation, migration, induced cell apoptosis, arrest the cell cycle in G1 phase and reversed drug resistance to PTX and CDDP in A549/PTX and A549/CDDP cell lines respectively. NUCkS1 is a direct target of miR-137, and is elevated in human lung cancer tissues, which is inversely correlated with miR-137 expression levels. miR-137 enhances the chemosensitivity of paclitaxel and cisplatin in vivo.

Key Molecule: Homeobox protein Hox-A5 (HOXA5) [333]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-196a was upregulated in human NSCLC tissues and cell lines; the downregulation of miR-196a (+) the sensitivity of NSCLC cell lines (SPC-A-1, A549) to DDP through the induction of apoptosis by targeting homeobox A5 (HOXA5). Taken together, these findings suggest that miR-196a is a valid therapeutic target with the potential to be employed as a novel multimodality therapy as part of a strategy for the treatment of patients with NSCLC.

Key Molecule: Hepatocyte nuclear factor 3-alpha (FOXA1) [334]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• In Vitro Model: 95C cells; Lung; Homo sapiens (Human); CVCL_7109
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic stable expression miR-194 suppressed proliferation, migration, invasion and metastasis and induced apoptosis in NSCLC cells and that this suppression could be reversed by reintroducing forkhead box A1 (FOXA1), a functional target of miR-194. In addition, miR-194 was downregulated in in cisplatin-resisted human NSCLC cell line-A549/DDP and overexpression of miR-194 increases cisplatin sensitivity.

Key Molecule: Clusterin (CLU) [335]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Anip973 cells; Lung; Homo sapiens (Human); CVCL_6879
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Altered expression of miR-378 in human lung adenocarcinoma cell lines with varying sensitivities to cDDP, and have shown that miR-378 can restore cDDP chemosensitivity in the human lung adenocarcinoma cells by targeting sCLU and downregulating Bcl-2, pCas-3, pErk1/2 and pAkt.

Key Molecule: TGF-beta receptor type I (TGFBR1) [336]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-BetaR1/Smad signaling pathway; Inhibition; hsa04350
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181b inhibited cell proliferation, augmented the chemosensitivity to DDP, suppressed migration and invasion in NSCLC cells miR-181b inhibited cell proliferation, augmented the chemosensitivity to DDP, suppressed migration and invasion in NSCLC cells in vitro and in vivo. Furthermore, miR-181b may increase chemosensitivity to DDP and suppress the invasion and metastasis of NSCLC cells through directly targeting the TGFbetaR1 signaling miR-181b may increase chemosensitivity to DDP and suppress the invasion and metastasis of NSCLC cells through directly targeting the TGFbetaR1 signaling pathway.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [337]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: HMGA2-E2F1-AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Decreased MicroRNA-26a expression significantly decreased the expression of E2F1, diminished Akt phosphorylation, and downregulated Bcl2 expression, which causes cisplatin resistance in human non-small cell lung cancer.

Key Molecule: Cellular tumor antigen p53 (TP53) [272]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Down-regulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway.The present study detected that the expression levels of Meg3 were significantly lower in cisplatin-resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. The results of the present study also demonstrated that the Meg3-mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, beta-catenin and survivin, which is a target gene of the WNT/beta-catenin signaling pathway.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [338]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The data showed a down-regulated of miR-148b expression and evaluated methyltransferases (DNMTs) expression in cisplatin-resisted human non-small cell lung cancer (NSCLC) cell line-A549/DDP and SPC-A1/DDP compared with their parental A549 and SPC-A1 cell line. In transfection experiments, miR-148b mimics reduced the DNMT1 expression, as well as (+) the sensitivity of cells to cisplatin and cisplatin-induced apoptosis in A549/DDP or SPC-A1/DDP cells. While miR-148b inhibitor increased DNMT1 expression, as well as attenuated the sensitivity of cells to cisplatin in A549 and SPC-A1 cells. miR-148b was showed to exert negative effect on DNMT1 expression by targeting its 3'UTR in A549/DDP and A549 cells. Importantly, silenced DNMT1 increases cisplatin sensitivity of A549/DDP cells and over-expressed DNMT1 reverses pro-apoptosis effect of miR-148b mimic.

Key Molecule: Cyclin-dependent kinase 8 (CDK8) [339]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The A549 cells transfected with miR-107 mimics were significantly more sensitive to the therapy of cisplatin than control cells. A549 cells Transfected with miR-107 mimics showed a decreased CDk8 protein expression. Down-regulation of CDk8 expression by siRNAs, A549 cells became more sensitive to the therapy of cisplatin. In addition, the (+) growth-inhibitory effect by the miR-107 mimic transfection was (+) after the addition of CDk8 siRNA. The present study provides the first evidence that miR-107 plays a key role in cisplatin resistance by targeting the CDk8 protein in NSCLC cell lines, suggesting that miR-107 can be used to predict a patient's response to chemotherapy as well as serve as a novel potential maker for NSCLC therapy.

Key Molecule: GTPase KRas (KRAS) [340]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-217 suppresses tumour development in lung cancer by targeting kRAS and enhances cell sensitivity to cisplatin.

Key Molecule: Secretagogin (SCGN) [341]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCL2 signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Knockdown of SCGN led to significantly increasing of chemosensitivity, which is similar to those induced by miR-494 mimics, and ectopic expression of SCGN could rescue the suppressive effect of miR-494.

Key Molecule: Apoptosis regulator BAX (BAX) [380]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Down-regulation of miR-21 inhibited growth, colony formation, antiapoptotic Bcl-2 expression and promoted proapoptotic Bax and caspase-9 expression in A549 cells treated with DDP. Upregulation of miR-21 promoted growth and colony formation in Sk-MES-1 cells treated with DDP. Furthermore, downregulation of miR-21 reduced growth of implanted tumors, suggesting that miR-21 inhibition could enhance the sensitivity of A549 cells to DDP in vivo. These data suggest an appropriate combination of DDP and miR-21 regulation might be a potential approach to lung cancer therapy. Combined DDP application with miR-21 downregulation for the treatment of lung cancer would help achieve effective treatment and reduce DDP side effects.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [380]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Down-regulation of miR-21 inhibited growth, colony formation, antiapoptotic Bcl-2 expression and promoted proapoptotic Bax and caspase-9 expression in A549 cells treated with DDP. Upregulation of miR-21 promoted growth and colony formation in Sk-MES-1 cells treated with DDP. Furthermore, downregulation of miR-21 reduced growth of implanted tumors, suggesting that miR-21 inhibition could enhance the sensitivity of A549 cells to DDP in vivo. These data suggest an appropriate combination of DDP and miR-21 regulation might be a potential approach to lung cancer therapy. Combined DDP application with miR-21 downregulation for the treatment of lung cancer would help achieve effective treatment and reduce DDP side effects.

Key Molecule: Caspase-9 (CASP9) [380]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Down-regulation of miR-21 inhibited growth, colony formation, antiapoptotic Bcl-2 expression and promoted proapoptotic Bax and caspase-9 expression in A549 cells treated with DDP. Upregulation of miR-21 promoted growth and colony formation in Sk-MES-1 cells treated with DDP. Furthermore, downregulation of miR-21 reduced growth of implanted tumors, suggesting that miR-21 inhibition could enhance the sensitivity of A549 cells to DDP in vivo. These data suggest an appropriate combination of DDP and miR-21 regulation might be a potential approach to lung cancer therapy. Combined DDP application with miR-21 downregulation for the treatment of lung cancer would help achieve effective treatment and reduce DDP side effects.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [342]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: H446/CDDP cells; Lung; Homo sapiens (Human); CVCL_RT21
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-137 was closely related to MDR of SCLC, and interference of miR-137 expression may attenuate drug resistant of H446/CDDP cells to cisplatin, partially through kIT expression regulation. kIT might be only one of the downstream molecules of miR-137 that related to SCLC MDR.

Key Molecule: Phosphatase and tensin homolog (PTEN) [344]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-92b promotes, while knockdown of it inhabits A549 cell growth, miR-92b regulates the resistance of NSCLC A549 cells to CDDP, Anti-miR-92b sensitizes A549/CDDP cells to CDDP-induced apop-tosis, miR-92b down-regulates PTEN expression at mRNA and protein level in A549 cells, PTEN plays important roles in cell cycle detention and apoptosis, regulation of cell adherence, migration, differentiation and has the function of enhancing the sensitivity of cancer cells to certain anticancer agents.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [345]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hsa-miR-135a/b could play a role in the development of CDDP resistance in lung cancer cell line at least in partby modulation of apoptosis via targeting MCL1.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [347]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SBC5 cells; Lung; Homo sapiens (Human); CVCL_1679
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cells pretreated with siR-Sirt1 are more sensitive to DDP than the control pretreated cells, miR-34a down-regulation Sirt1 and sensitizes lung cancer cell lines to DDP.

Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [348]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Apaf-1 is a core molecule in the mitochondrial apoptotic pathway, relaying the death signal to the heptameric apoptosome complex to ignite the downstream cascade of caspases. Down-regulation of miR-155 could enhance the sensitivity of A549 cells to cisplatin treatment via restoration of the Apaf-1 pathway.

Key Molecule: Glutathione S-transferase P (GSTP1) [349]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: GSTP1 augment drug resistance by catalyzing GSH-drug binding, exogenous miR-513a-3p plays a role in sensitizing human lung adenocarcinoma cell lines to cisplatin by repressing GSTP1 expression at the translational level.

Key Molecule: Fibroblast growth factor 9 (FGF9) [353]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR-219a-5p enhances cisplatin sensitivity of human non-small cell lung cancer by targeting FGF9.

Key Molecule: DNA-binding protein inhibitor ID-1 (ID1) [354]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR381 suppresses the growth and increases cisplatin sensitivity in non-small cell lung cancer cells through inhibition of nuclear factor-kB signaling. miR381 suppresses the activation of NF-kB signaling by targeting ID1.

Key Molecule: Transcription factor Jun (JUN) [355]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: c-Jun/BCL-xl signaling pathway; Inhibition; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR216b sensitizes NSCLC cells to cisplatin-induced apoptosis by decreasing the expression of c-Jun and inhibiting the c-Jun/Bcl-xl pathway.

Key Molecule: Heterogeneous nuclear ribonucleoprotein U (HNRNPU) [356]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vitro Model: A549-DDP cells; Lung; Homo sapiens (Human); CVCL_IP03
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS Cell Proliferation Assay; EdU assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA SFTA1P promoted apoptosis and increased cisplatin chemosensitivity via regulating the hnRNP-U-GADD45A axis in lung squamous cell carcinoma. SFTA1P could up-regulate hnRNP-U expression. hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [266]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: lncRNA-XIST/miR17 axis; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of LncRNA-XIST enhances the chemosensitivity of NSCLC cells via suppression of autophagy. LncRNA-XIST inhibits the expression of miR17 to modulate ATG7 and LncRNA-XIST regulates autophagy through ATG7.

Key Molecule: Beclin-1 (BECN1) [358]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: Letp cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; WB assay; Colony formation assay; Fow cytometric analysis
• Mechanism Description: Beclin-1-dependent autophagy in SCLC was directly regulated by miR30a-5p. miR30a-5p contributed to chemoresistance of SCLC cells partially in an Beclin-1-dependent manneRNA.

Key Molecule: Protein FAM168A (TCRP1) [359]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/NF-kB signaling pathway; Activation; hsa04151
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: 95D cells; Lung; Homo sapiens (Human); CVCL_7110
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: Epigenetic silencing of miR493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1). TCRP1 mediated a specific resistance to cDDP part due to activation of the PI3k/Akt/NF-kB signaling pathway.

Key Molecule: Cellular tumor antigen p53 (TP53) [360]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53/p66shc signaling pathway; Activation; hsa04115
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Downregulated long non-coding RNA TRPM2-AS inhibits cisplatin resistance of non-small cell lung cancer cells via activation of p53- p66shc pathway.

Key Molecule: SHC-transforming protein 1 (SHC1) [360]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53/p66shc signaling pathway; Activation; hsa04115
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Downregulated long non-coding RNA TRPM2-AS inhibits cisplatin resistance of non-small cell lung cancer cells via activation of p53- p66shc pathway.

Key Molecule: Pyruvate kinase M2 (PKM) [379]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR133b can inhibit the growth and proliferation of lung cancer stem cells by down regulating PkM2, and can enhance the sensitivity of lung cancer stem cells to DDP.

Key Molecule: Protein delta homolog 1 (DLK1) [361]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay; DAPI staining assay
• Mechanism Description: miR129-5p inhibits non-small cell lung cancer cell stemness and chemoresistance through targeting DLk1.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [362]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Upregulation of miR7 increases the sensitivity of LA cells to CDDP via induction of apoptosis by targeting Bcl-2.

Key Molecule: Myocyte-specific enhancer factor 2D (MEF2D) [364]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; LDH assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR1244 suppressed cell viability and increased LDH toxicity in cisplatin-treated A549 and NCI-H522 cells and induced the apoptosis of cisplatin-treated A549 and NCI-H522 cells. Overexpression of miR1244 promoted caspase-3 activity and p53 and Bax protein expression, and suppressed MEF2D and cyclin D1 protein expression in cisplatin treated A549 and NCI-H522 cells.

Key Molecule: High mobility group protein B1 (HMGB1) [365]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: 16HBE cells; Lung; Homo sapiens (Human); CVCL_0112
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Caspase-3 and TUNEL staining assay; MTT assay
• Mechanism Description: miR142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3k/Akt/mTOR pathway. miR142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo.

Key Molecule: Dickkopf-related protein 1 (DKK1) [366]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NHBE cells; Lung; Homo sapiens (Human); CVCL_S124
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Caspase 3/7 apoptosis assay
• Mechanism Description: Overexpression of miR203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1.

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [367]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: NCl-H1792 cells; Lung; Homo sapiens (Human); CVCL_1495
• In Vitro Model: NCl-H1944 cells; Lung; Homo sapiens (Human); CVCL_1508
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoprecipitation assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: piR-L-138 directly interacted with p60-MDM2 and inhibited CDDP-activated apoptosis in p53-mutated LSCC.

Key Molecule: Tetraspanin-12 (TSN12) [387]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: NCI-H69 cells; Lung; Homo sapiens (Human); CVCL_1579
• In Vitro Model: NCI-H69AR cells; Lung; Homo sapiens (Human); CVCL_3513
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V/propidium iodide detection assay; Scratch healing test
• Mechanism Description: TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR495, and TSPAN12 is negatively regulated by miR495.

Key Molecule: Cyclin-J (CCNJ) [368]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: A549/DDP cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1/DDP cells; Kidney; Homo sapiens (Human); CVCL_6955
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell migration assay; Flow cytometric analysis
• Mechanism Description: Up-regulation of miR146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J.

Key Molecule: DNA polymerase zeta catalytic subunit (REV3L) [370]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: microRNA 29a enhances cisplatin sensitivity in non small cell lung cancer through the downregulation of REV3L.

Key Molecule: GTPase KRas (KRAS) [371]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Inhibition; hsa04010
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H441 cells; Lung; Homo sapiens (Human); CVCL_1561
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The overexpression of miR-202 was found to inhibit the Ras/MAPk pathway by targeting the kRas gene.

Key Molecule: Neurogenic locus notch homolog protein 2 (NOTCH2) [372]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch2/HES1 signaling pathway; Inhibition; hsa04330
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Ectopic miR-181b expression suppressed cancer stem cell properties and enhanced sensitivity to cisplatin (DDP) treatment by directly targeting Notch2.

Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [373]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; EdU assay
• Mechanism Description: microRNA-9 Enhanced Cisplatin Sensitivity in Nonsmall Cell Lung Cancer Cells by downregulating Eukaryotic Translation Initiation Factor 5A2.

Key Molecule: Zinc finger protein SNAI2 (SNAI2) [374]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/Slug signaling pathway; Regulation; hsa04010
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: LncRNA NNT-AS1 is a major mediator of cisplatin chemoresistance in non-small cell lung cancer through MAPk/Slug pathway.

Key Molecule: Ubiquitin-like-conjugating enzyme ATG3 (ATG3) [375]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-1 enhanced DDP sensitivity of DDP resistant NSCLC cells by downregulating ATG3.

Key Molecule: Phosphatase and tensin homolog (PTEN) [377]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: miR18a/PTEN signaling pathway; Regulation; hsa05206
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TP53TG1 increased the sensitivity of NSCLC cells to cisplatin by modulating miR-18a/PTEN axis by promoting PTEN expression via inhibiting miR-18a.

Key Molecule: GTPase Nras (NRAS) [378]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Caspase-3 Activity Assay
• Mechanism Description: miR-29a renders lung cancer cells more sensitive to cisplatin treatment and miR-29a and cisplatin combination promoted apoptotic effect through targeting NRAS in lung cancer cells.

Key Molecule: Dual specificity protein phosphatase 1 (DUSP1) [388]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In non-small cell lung cancer (NSCLC) cells and xenografts, MkP-1 knockdown triggered the down-regulation of the metabolic enzymes and cytoprotective proteins, which are the target genes of Nrf2. Consequently, the cell growth was markedly inhibited with decrease of tumor metabolisms and GSH contents. Moreover, MkP-1 silencing sensitized NSCLC cells to cisplatin treatment. Mechanistically, MkP-1 inhibited the ubiquitylation of Nrf2 via a direct interaction with the transcription factor. Thus, MkP-1 and Nrf2 form a forward feedback loop in lung cancer cells, which stabilizing and activating Nrf2 to promote anabolic metabolism and GSH biosynthesis.

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [91], [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung large cell carcinoma [ICD-11: 2C25.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. And overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [214], [213]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. And the antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Key Molecule: G3BP stress granule assembly factor 1 (G3BP1) [389]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung small cell carcinoma [ICD-11: 2C25.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Small-cell lung cancer cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knocking down the expression of G3BP1 significantly increased the sensitivity of SCLC cells to cisplatin.

Pleural mesothelioma [ICD-11: 2C26]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Pvt1 oncogene (PVT1) [25]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: NCI-H2052 cells; Lung; Homo sapiens (Human); CVCL_1518
• In Vitro Model: NCI-H2452 cells; Lung; Homo sapiens (Human); CVCL_1553
• In Vitro Model: NCI-H28 cells; Lung; Homo sapiens (Human); CVCL_1555
• In Vitro Model: HCT-4012 cells; Lung; Homo sapiens (Human); CVCL_IT30
• In Vitro Model: HP10 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: HP3 cells; Lung; Homo sapiens (Human); CVCL_C311
• In Vitro Model: HP5 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: HP7 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: HP9 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: MET-5A cells; Lung; Homo sapiens (Human); CVCL_3749
• In Vitro Model: Meso cells; Lung; Homo sapiens (Human); CVCL_5759
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: c-Myc and PVT1 co-amplification is frequent in MPM. C-MYC and PVT1 cooperation helps to stimulate proliferation, decrease sensitivity to platinum therapy, and reduce apoptosis. Both genes also help to regulate apoptosis-related genes, with C-MYC revealing a tendency to maintain a balance between pro-apoptotic and anti-apoptotic genes, whereas PVT1 revealed a tendency to upregulate pro-apoptotic genes and downregulate anti-apoptotic genes, thereby helping to suppress apoptosis.

Key Molecule: hsa-mir-15a [390]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SYBR Green-based assay
• Mechanism Description: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only.

Key Molecule: hsa-mir-15a [390]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SYBR Green-based assay
• Mechanism Description: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only.

Key Molecule: hsa-mir-16 [390]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SYBR Green-based assay
• Mechanism Description: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only.

Key Molecule: hsa-mir-16 [390]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SYBR Green-based assay
• Mechanism Description: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only.

Key Molecule: Forkhead box protein O3 (FOXO3) [390]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SYBR Green-based assay
• Mechanism Description: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only.

Key Molecule: Forkhead box protein O3 (FOXO3) [390]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SYBR Green-based assay
• Mechanism Description: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Myc proto-oncogene protein (MYC) [25]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant pleural mesothelioma [ICD-11: 2C26.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: NCI-H2052 cells; Lung; Homo sapiens (Human); CVCL_1518
• In Vitro Model: NCI-H2452 cells; Lung; Homo sapiens (Human); CVCL_1553
• In Vitro Model: NCI-H28 cells; Lung; Homo sapiens (Human); CVCL_1555
• In Vitro Model: HCT-4012 cells; Lung; Homo sapiens (Human); CVCL_IT30
• In Vitro Model: HP10 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: HP3 cells; Lung; Homo sapiens (Human); CVCL_C311
• In Vitro Model: HP5 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: HP7 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: HP9 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: MET-5A cells; Lung; Homo sapiens (Human); CVCL_3749
• In Vitro Model: Meso cells; Lung; Homo sapiens (Human); CVCL_5759
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: c-Myc and PVT1 co-amplification is frequent in MPM. C-MYC and PVT1 cooperation helps to stimulate proliferation, decrease sensitivity to platinum therapy, and reduce apoptosis. Both genes also help to regulate apoptosis-related genes, with C-MYC revealing a tendency to maintain a balance between pro-apoptotic and anti-apoptotic genes, whereas PVT1 revealed a tendency to upregulate pro-apoptotic genes and downregulate anti-apoptotic genes, thereby helping to suppress apoptosis.

Melanoma [ICD-11: 2C30]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-301 [18]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/FAKT signaling pathway; Activation; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
• Mechanism Description: PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.

Key Molecule: hsa-mir-211 [391]

• Molecule Alteration: Methylation; Down-regulation
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpressed 211 could enhance the anticancer effect of cisplatin and restoration of miR-211 rendered susceptibility to cisplatin in cisplatin-resistant cells.miR-211 could be transcriptionally repressed by EZH2 mediated promoter methylation.

Key Molecule: hsa-miR-30a-5p [40]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/P53 signaling pathway; Regulation; hsa04151
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: M8 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: Sk-Mel-19 cells; Skin; Homo sapiens (Human); CVCL_6025
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-30a-5p was over-expressed in cisplatin resistant melanoma cells and could influence the activity of PI3k/AkT and the protein level of P53 by targeting IGF1R gene.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [18]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/FAKT signaling pathway; Activation; hsa04151
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: SkMEL1 cells; Skin; Homo sapiens (Human); CVCL_0068
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Annexin V-fluorescein isothiocyanate (FITC) apoptosis analysis; Wound scratch healing or transwell invasion assay
• Mechanism Description: PTEN can interact with AkT and FAk and inhibit their activity through their dephosphorylation, Akt and FAk signaling pathways are involved in miR301a/PTEN-promoting malignant phenotypes in MM cells, miR301a promotes MM progression via activation of Akt and FAk signaling pathways by down regulating PTEN.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [391]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpressed 211 could enhance the anticancer effect of cisplatin and restoration of miR-211 rendered susceptibility to cisplatin in cisplatin-resistant cells.miR-211 could be transcriptionally repressed by EZH2 mediated promoter methylation.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [40]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/P53 signaling pathway; Regulation; hsa04151
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: M8 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: Sk-Mel-19 cells; Skin; Homo sapiens (Human); CVCL_6025
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-30a-5p was over-expressed in cisplatin resistant melanoma cells and could influence the activity of PI3k/AkT and the protein level of P53 by targeting IGF1R gene.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-488-3p [392]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• In Vitro Model: HEMn-LP cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM451 cells; Skin; Homo sapiens (Human); CVCL_6357
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: microRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRkDC.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA-dependent catalytic protein kinase (PRKDC) [392]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: Sk-Mel28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• In Vitro Model: HEMn-LP cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: WM451 cells; Skin; Homo sapiens (Human); CVCL_6357
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: microRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRkDC.

Skin squamous cell carcinoma [ICD-11: 2C31]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-15 [393]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Key Molecule: hsa-mir-16 [393]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Key Molecule: hsa-mir-195 [393]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Key Molecule: hsa-mir-424 [393]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Key Molecule: hsa-mir-497 [393]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase Chk1 (CHK1) [393]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Key Molecule: Wee1-like protein kinase (WEE1) [393]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Epidermoid carcinoma [ICD-11: 2C31.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: KB-3-1 cells; Lung; Homo sapiens (Human); CVCL_2088
• In Vitro Model: KB-CP.5 cells; Lung; Homo sapiens (Human); CVCL_IP04
• In Vitro Model: KB-CP20 cells; Lung; Homo sapiens (Human); CVCL_IP06
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of the cell cycle kinases WEE1 and CHk1 occurred commonly in cisplatin-resistant cells, miR-15/16/195/424/497 family sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHk1.

Sarcoma [ICD-11: 2C35]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [47]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) [47]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Key Molecule: Myc proto-oncogene protein (MYC) [47]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Key Molecule: Transcription factor SOX-2 (SOX2) [47]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Key Molecule: Catenin beta interacting protein 1 (CTNNBIP1) [47]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW-872 cells; Skin; Homo sapiens (Human); CVCL_1730
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• In Vitro Model: TE-671 cells; Peripheral blood; Homo sapiens (Human); CVCL_1756
• In Vitro Model: SW-684 cells; Skin; Homo sapiens (Human); CVCL_1726
• In Vitro Model: SW-982 cells; Testicular; Homo sapiens (Human); CVCL_1734
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: By investigating of important regulators of stem cell biology, real-time RT-PCR data showed an increased expression of c-Myc, beta-catenin, and SOX-2 in the ALDH1high population and a significant higher level of ABCG2. Statistical analysis of data demonstrated that ALDH1high cells of SW-982 and SW-1353 showed higher resistance to commonly used chemotherapeutic agents like doxorubicin, epirubicin, and cisplatin than ALDH1low cells. This study demonstrates that in different sarcoma cell lines, high ALDH1 activity can be used to identify a subpopulation of cells characterized by a significantly higher proliferation rate, increased colony forming, increased expression of ABC transporter genes and stemness markers compared to control cells. In addition, enhanced drug resistance was demonstrated.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [394]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Sarcoma [ICD-11: 2C35.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: High level expression of both of MTDH/AEG1 and HOTAIR in the primary tumor correlated with a likelihood to metastasize.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Bcl-2-interacting killer (BIK) [31]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF-7R cells; Breast; Homo sapiens (Human); CVCL_Y493
• In Vitro Model: ZR-75-1R cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V apoptosis assay; Fow cytometry analysis
• Mechanism Description: LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIk and NOXA.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [31]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF-7R cells; Breast; Homo sapiens (Human); CVCL_Y493
• In Vitro Model: ZR-75-1R cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V apoptosis assay; Fow cytometry analysis
• Mechanism Description: LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIk and NOXA.

Key Molecule: Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) [31]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF-7R cells; Breast; Homo sapiens (Human); CVCL_Y493
• In Vitro Model: ZR-75-1R cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V apoptosis assay; Fow cytometry analysis
• Mechanism Description: LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIk and NOXA.

Key Molecule: hsa-let-7i [6]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reduced let-7i expression significantly increased the resistance of ovarian and breast cancer cells to the chemotherapy drug, cis-platinum.

Key Molecule: hsa-mir-105 [395]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vitro Model: BT-483 cells; Breast; Homo sapiens (Human); CVCL_2319
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: DU4475 cells; Breast; Homo sapiens (Human); CVCL_1183
• In Vitro Model: HCC1599 cells; Breast; Homo sapiens (Human); CVCL_1256
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR105/93-3p activates Wnt/beta-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells.

Key Molecule: hsa-miR-93-3p [395]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vitro Model: BT-483 cells; Breast; Homo sapiens (Human); CVCL_2319
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: DU4475 cells; Breast; Homo sapiens (Human); CVCL_1183
• In Vitro Model: HCC1599 cells; Breast; Homo sapiens (Human); CVCL_1256
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR105/93-3p activates Wnt/beta-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells.

Key Molecule: hsa-mir-24 [396]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FIH1/HIFalpha signaling pathway; Regulation; hsa04066
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Caspase-Glo 3/7 Assay; Transwell migration assay
• Mechanism Description: miR24 increases under hypoxic conditions, causing downregulation of FIH1 and upregulation of HIF1alpha. miR24 hampers chemotherapy-induced apoptosis in breast CSCs and increases cell resistance to hypoxic conditions through an FIH1 HIFalpha pathway.

Key Molecule: hsa-miR-106a-3p [397]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-106a promotes breast cancer cell proliferation and invasion through upregulation of Bcl-2, ABCG2, and P53, and downregulation of Bax and RUNX3.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [397]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Activation; hsa04110
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-106a promotes breast cancer cell proliferation and invasion through upregulation of Bcl-2, ABCG2, and P53, and downregulation of Bax and RUNX3.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Secreted frizzled-related protein 1 (SFRP1) [395]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: AU565 cells; Breast; Homo sapiens (Human); CVCL_1074
• In Vitro Model: BT-483 cells; Breast; Homo sapiens (Human); CVCL_2319
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: DU4475 cells; Breast; Homo sapiens (Human); CVCL_1183
• In Vitro Model: HCC1599 cells; Breast; Homo sapiens (Human); CVCL_1256
• In Vitro Model: HCC1806 cells; Breast; Homo sapiens (Human); CVCL_1258
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• In Vitro Model: HCC70 cells; Breast; Homo sapiens (Human); CVCL_1270
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR105/93-3p activates Wnt/beta-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells.

Key Molecule: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) [396]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FIH1/HIFalpha signaling pathway; Regulation; hsa04066
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 Assay; Transwell migration assay
• Mechanism Description: miR24 increases under hypoxic conditions, causing downregulation of FIH1 and upregulation of HIF1alpha. miR24 hampers chemotherapy-induced apoptosis in breast CSCs and increases cell resistance to hypoxic conditions through an FIH1 HIFalpha pathway.

Key Molecule: Runt-related transcription factor 3 (RUNX3) [397]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-106a promotes breast cancer cell proliferation and invasion through upregulation of Bcl-2, ABCG2, and P53, and downregulation of Bax and RUNX3.

Key Molecule: Ubiquitin protein ligase E3 component n-recognin 5 (UBR5) [398]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: High nuclear EDD expression in a cohort of 151 women with serous ovarian carcinoma was associated with an increased risk of disease recurrence following first-line chemotherapy, and siRNA-knockdown of EDD gene expression partially restored cisplatin sensitivity in cisplatin-resistant ovarian cancer cells in vitro. Loss of EDD induced cell-cycle arrest at G1 through upregulation of tumour suppressor p53 and p21 proteins in osteosarcoma cells in vitro.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-223 [399]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MDA-MB-435 cells; Breast; Homo sapiens (Human); CVCL_0417
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; FITC-Annexin V and PI staining assay; Flow cytometry assay
• Mechanism Description: microRNA-223 increases the sensitivity of triple-negative breast cancer stem cells to TRAIL-induced apoptosis by targeting HAX-1.

Key Molecule: hsa-mir-302b [400]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Trypan blue stain assay
• Mechanism Description: miR-302b overexpression enhances sensitivity to cisplatin in breast cancer cell lines, reducing cell viability and proliferation in response to the treatment. We also identified E2F1, a master regulator of the G1/S transition, as a direct target gene of miR-302b. E2F1 transcriptionally activates ATM, the main cellular sensor of DNA damage. Through the negative regulation of E2F1, miR-302b indirectly affects ATM expression, abrogating cell-cycle progression upon cisplatin treatment. Moreover miR-302b, impairs the ability of breast cancer cells to repair damaged DNA, enhancing apoptosis activation following cisplatin treatment.

Key Molecule: hsa-mir-134 [401]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: When delivered directly by transfection the STAT5B and Hsp90 expression levels were reduced, but response to anti-Hsp90 drugs was not augmented. However, cellular growth was reduced and cisplatin-induced apoptosis was (+). Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90 expression, had no apparent effects on proliferation, but cellular migration and invasion were reduced and sensitivity to anti-Hsp90 drugs was (+).

Key Molecule: hsa-miR-638 [402]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA damage repair signaling pathway; Inhibition; hsa03410
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Matrigel invasion assay
• Mechanism Description: miR-638 overexpression increased sensitivity to DNA-damaging agents, ultraviolet (UV) and cisplatin.

Key Molecule: hsa-miR-342-3p [403]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Triple-negative breast cancer with high expression of miR-342-3p is more sensitive to chemotherapy drugs, and miR-342-3p can regulate the chemotherapy sensitivity of breast cancer cell line MDA-MB-231 to paclitaxel and cisplatin.

Key Molecule: hsa-mir-30d [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-103 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-mir-133a [404]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/DOX cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: CVCL_4V97; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Targeted downregulation of overexpressed FTL protein by microRNA miR-133a increases the sensitivity of drug-resistant cells to doxorubicin and cisplatin.

Key Molecule: hsa-mir-96 [91]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: hsa-mir-203 [405]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: ZR-75 cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Overexpression of SOCS3 could efficiently enhance cisplatin-mediated cell cytotoxicity in breast cancer cells. SOCS3 expression is significantly higher in miR-203 knockdown cisplatin-treated MCF-7 cells, thus cause the resistance to cisplatin.

Key Molecule: hsa-mir-30a [254]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: hsa-mir-519d [406]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MCL-1 dependent mitochondria signaling pathway; Activation; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR519d impedes cisplatin-resistance in breast cancer stem cells by down-regulating the expression of MCL-1.

Key Molecule: hsa-miR-199a-3p [407]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-231/DDP cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC apoptosis assay
• Mechanism Description: miR199a-3p enhances breast cancer cell sensitivity to cisplatin by downregulating TFAM.

Key Molecule: hsa-mir-381 [408]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-381 could overcome DDP resistance of breast cancer by directly targeting MDR1.

Key Molecule: hsa-mir-197 [409]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA TUG1 sensitized triple negative breast cancer to cisplatin by upregulating NLk expression via sponging miR-197.

Key Molecule: Taurine up-regulated 1 (TUG1) [409]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA TUG1 sensitized triple negative breast cancer to cisplatin by upregulating NLk expression via sponging miR-197.

Key Molecule: hsa-mir-1307 [410]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Repression of MDM4 in drug-resistant cells is essential for miR-1307-induced restoration of chemosensitivity.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [408]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-381 could overcome DDP resistance of breast cancer by directly targeting MDR1.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: C-terminal-binding protein 1 (CTBP1) [411]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR644a/CTBP1/p53 signaling pathway; Activation; hsa05206
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MCF-12A cells; Breast; Homo sapiens (Human); CVCL_3744
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: RTCA proliferation and migration assay; Promega assay
• Mechanism Description: miR-644a directly targets transcriptional co-repressor CTBP1 and thereby upregulates p53 levels and the miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer.

Key Molecule: hsa-miR-644a [411]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR644a/CTBP1/p53 signaling pathway; Activation; hsa05206
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MCF-12A cells; Breast; Homo sapiens (Human); CVCL_3744
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: RTCA proliferation and migration assay; Promega assay
• Mechanism Description: miR-644a directly targets transcriptional co-repressor CTBP1 and thereby upregulates p53 levels and the miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer.

Key Molecule: Polycomb complex protein BMI-1 (BMI1) [412]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: MDAMB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assay; BrdU assay; MTT assay
• Mechanism Description: Overexpressing miR-15a sensitizes MDAMB-231 cells to the chemotherapeutic drug cisplatin via inhibiting BMI1 and downregulating MET.

Key Molecule: hsa-mir-15 [412]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: MDAMB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: TUNEL assay; BrdU assay; MTT assay
• Mechanism Description: Overexpressing miR-15a sensitizes MDAMB-231 cells to the chemotherapeutic drug cisplatin via inhibiting BMI1 and downregulating MET.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: HCLS1-associated protein X-1 (HAX1) [399]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MDA-MB-435 cells; Breast; Homo sapiens (Human); CVCL_0417
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; FITC-Annexin V and PI staining assay; Flow cytometry assay
• Mechanism Description: microRNA-223 increases the sensitivity of triple-negative breast cancer stem cells to TRAIL-induced apoptosis by targeting HAX-1.

Key Molecule: Transcription factor E2F1 (E2F1) [400]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Trypan blue stain assay
• Mechanism Description: miR-302b overexpression enhances sensitivity to cisplatin in breast cancer cell lines, reducing cell viability and proliferation in response to the treatment. We also identified E2F1, a master regulator of the G1/S transition, as a direct target gene of miR-302b. E2F1 transcriptionally activates ATM, the main cellular sensor of DNA damage. Through the negative regulation of E2F1, miR-302b indirectly affects ATM expression, abrogating cell-cycle progression upon cisplatin treatment. Moreover miR-302b, impairs the ability of breast cancer cells to repair damaged DNA, enhancing apoptosis activation following cisplatin treatment.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [401]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: When delivered directly by transfection the STAT5B and Hsp90 expression levels were reduced, but response to anti-Hsp90 drugs was not augmented. However, cellular growth was reduced and cisplatin-induced apoptosis was (+). Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90 expression, had no apparent effects on proliferation, but cellular migration and invasion were reduced and sensitivity to anti-Hsp90 drugs was (+).

Key Molecule: Heat shock protein HSP 90 (HSP90 ) [401]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: When delivered directly by transfection the STAT5B and Hsp90 expression levels were reduced, but response to anti-Hsp90 drugs was not augmented. However, cellular growth was reduced and cisplatin-induced apoptosis was (+). Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90 expression, had no apparent effects on proliferation, but cellular migration and invasion were reduced and sensitivity to anti-Hsp90 drugs was (+).

Key Molecule: Signal transducer activator transcription 5B (STAT5B) [401]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: When delivered directly by transfection the STAT5B and Hsp90 expression levels were reduced, but response to anti-Hsp90 drugs was not augmented. However, cellular growth was reduced and cisplatin-induced apoptosis was (+). Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90 expression, had no apparent effects on proliferation, but cellular migration and invasion were reduced and sensitivity to anti-Hsp90 drugs was (+).

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [402]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA damage repair signaling pathway; Inhibition; hsa03410
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Matrigel invasion assay
• Mechanism Description: miR-638 overexpression increased sensitivity to DNA-damaging agents, ultraviolet (UV) and cisplatin.

Key Molecule: Beclin-1 (BECN1) [58]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: Ferritin light chain (FTL) [404]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/DOX cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: CVCL_4V97; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Targeted downregulation of overexpressed FTL protein by microRNA miR-133a increases the sensitivity of drug-resistant cells to doxorubicin and cisplatin.

Key Molecule: DNA repair protein REV1 (REV1) [91]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: Suppressor of cytokine signaling 3 (SOCS3) [405]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: ZR-75 cells; Breast; Homo sapiens (Human); CVCL_0588
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Overexpression of SOCS3 could efficiently enhance cisplatin-mediated cell cytotoxicity in breast cancer cells. SOCS3 expression is significantly higher in miR-203 knockdown cisplatin-treated MCF-7 cells, thus cause the resistance to cisplatin.

Key Molecule: Beclin-1 (BECN1) [254]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [406]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MCL-1 dependent mitochondria signaling pathway; Activation; hsa04210
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR519d impedes cisplatin-resistance in breast cancer stem cells by down-regulating the expression of MCL-1.

Key Molecule: Transcription factor A (TFAM) [407]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-231/DDP cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC apoptosis assay
• Mechanism Description: miR199a-3p enhances breast cancer cell sensitivity to cisplatin by downregulating TFAM.

Key Molecule: Serine/threonine-protein kinase NLK (NLK) [409]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA TUG1 sensitized triple negative breast cancer to cisplatin by upregulating NLk expression via sponging miR-197.

Key Molecule: Protein Mdm4 (MDM4) [410]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Repression of MDM4 in drug-resistant cells is essential for miR-1307-induced restoration of chemosensitivity.

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [91], [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. And overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Breast invasive carcinoma [ICD-11: 2C61]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-96 [91]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast ductal carcinoma [ICD-11: 2C61.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein REV1 (REV1) [91]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast ductal carcinoma [ICD-11: 2C61.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC1937 cells; Breast; Homo sapiens (Human); CVCL_0290
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Ovarian cancer [ICD-11: 2C73]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutathione S-transferase P (GSTP1) [414]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-30a-5p [415]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: COC1/DDP cells; Ovary; Homo sapiens (Human); CVCL_6892
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miRNA-30a-5p was able to promote cell growth and colony forming ability, and enhance cell migration and invasion.

Key Molecule: hsa-miR-770-5p [416]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• Experiment for Molecule Alteration: qRT-PCR; ISH
• Experiment for Drug Resistance: Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting and reducing the level of ERCC2.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Pvt1 oncogene (PVT1) [417]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: hsa-mir-130a [418]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: hsa-mir-374a [418]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: hsa-miR-21-3p [419]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Several miRNAs that are increased in cisplatin-resistant cells. We show that most of these do not directly contribute to cisplatin resistance. Interestingly, miR-21-3p, the passenger strand of the known oncomiR, directed increased resistance to cisplatin in a range of ovarian cell lines. This effect was specific to the star strand, as miR-21-5p had the opposite effect and actually increased sensitivity of A2780 cells to cisplatin. We identify NAV3 as a potential target of miR-21-3p and show that knockdown of NAV3 increases resistance.

Key Molecule: hsa-mir-128a [420]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: hsa-miR-224-5p [421]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian papillary serous carcinoma [ICD-11: 2C73.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PRKCD signaling pathway; Inhibition; hsa05208
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: PRkCD, known as protein kinase C deta, is a PkC isozyme that acts as a substrate for caspase-3. Its activity is believed to be required for apoptosis induced by DNA damaging agents such as cisplatin, mitomycin C and doxorubicin. miR-224-5p could negatively regulate the expression of PRkCD, and together with PRkCD, they can serve as novel predictors and prognostic biomarkers for OPSC patient response to overall disease-specific survival. The PRkCD pathway may be a molecular mechanism through which miR-224-5p exerts its functions as an oncogene and enhancer of chemoresistance to cisplatin in OPSC patients.

Key Molecule: hsa-mir-21 [422]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk1/c-Jun pathway; Activation; hsa04010
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vitro Model: A2780CP20 cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Alamar blue dye assay
• Mechanism Description: Blocking the JNk-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNk-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.

Key Molecule: hsa-mir-489 [423]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 overexpression results in an inhibition of SkOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SkOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SkOV3, OVCAR3, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression.

Key Molecule: hsa-miR-199b-5p [424]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JAG1/Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The forced expression of miR-199b-5p could suppress ovarian cancer cell growth and sensitize the cells to cisplatin-induced cytotoxicity. On the other hand, as a direct target of miR-199b-5p in ovarian cancer cells, JAG1 depletion by siRNAs also resulted in cell growth retardation and sensitization to cisplatin-induced cytotoxicity. In contrast, activating Notch1 signaling by JAG1 or repressing miR-199b-5p by anti-miR-199b-5p could induce the activity of JAG1-Notch1 signaling in ovarian cancer cells. The loss of miR-199b-5p increased the activation of JAG1-Notch1 signaling, which in turn promoted ovarian cancer progression and acquired chemoresistance.

Key Molecule: hsa-mir-21 [425]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780-CP cells; Ovary; Homo sapiens (Human); CVCL_H745
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The inhibition of miR-21 enhanced the sensitivity of ovarian cancer cells to cisplatin, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, downregulation of PDCD4 results in drug resistance via enhanced expression of c-IAP2 and MDR1.

Key Molecule: hsa-mir-106a [426]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The enhancement of miR-106a expression contributes to the generation of CDDP-resistant ovarian cancer cells, partly by targeting PDCD4. PDCD4 promoted CDDP-induced apoptosis mainly through the death receptor-mediated pathway.

Key Molecule: hsa-mir-106a [427]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of miR-106a dramatically decreased antiproliferative effects and apoptosis in-duced by cisplatin in A2780 cells, while overexpression of miR-106a significantly increased antiprolif-erative effects and apoptosis induced by cisplatin in A2780/DDP cells. Furthermore, miR-106a inhibited cell survival and cisplatin resistance through downregulating the expression of Mcl-1. Mcl-1 was a di-rect target of miR-106a.

Key Molecule: hsa-mir-29a [428]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-29b [428]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-29c [428]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-146a [429]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Higher expression of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease.

Key Molecule: hsa-mir-150 [429]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Higher expression of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease.

Key Molecule: hsa-mir-141 [430]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780 DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-141 regulates the expression of kEAP1 and that the repression of kEAP1 contributes to cisplatin resistance. Inhibition of NF-kB signaling enhances miR-141-mediated cisplatin sensitivity.

Key Molecule: hsa-mir-130a [431]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/PTEN/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CIS cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-130a, acting as an intermediate, might regulate cisplatin resistance by activating PI3k/Akt/PTEN/mTOR and ABC superfamily drug transporter pathways in ovarian cancer cells.

Key Molecule: hsa-mir-93 [432]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-93, a new family member of PTEN regulator, blocks PTEN translation leading to activation of the AkT pathway and played an important role in regulating cisplatin chemosensitivity pathway in ovarian cancer.

Key Molecule: hsa-mir-125b [433]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bak1 was a direct target of miR-125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. miR-125b has a sig-nificantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression.

Key Molecule: hsa-mir-376c [434]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Nodal/ALK7 signaling pathway; Inhibition; hsa04350
• Cell Pathway Regulation: Spheroid formation; Activation; hsa04140
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: We found that miR-376c increased cell proliferation and survival, as well as spheroid formation, in part by targeting ALk7. We have also provided evidence that the Nodal-ALk7 pathway is involved in cisplatin-induced ovarian cancer cell death and that miR-376c might promote chemoresistance.

Key Molecule: hsa-mir-214 [435]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-214 induces cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3'-UTR largely abrogates miR-214-induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.

Key Molecule: X inactive specific transcript (XIST) [23]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vitro Model: OVCA3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: OVCA633 cells; Ovary; Homo sapiens (Human); CVCL_W776
• In Vitro Model: OVCA680 cells; Ovary; Homo sapiens (Human); CVCL_W781
• In Vitro Model: OVCA702 cells; Ovary; Homo sapiens (Human); CVCL_W782
• In Vitro Model: OVCA810 cells; Ovary; Homo sapiens (Human); CVCL_W783
• Experiment for Molecule Alteration: qPCR; Microarray assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: One possible down-stream candidate is XIAP, which is the most potent direct inhibitor of caspases and apoptosis among all human IAP family proteins. Down-regulated expression of XIAP has been shown to induce apoptosis in chemoresistant human ovarian cancer cells. Down-regulation of XIST might increase the expression level of XIAP and block drug-induced apoptosis to cause resistance phenotype.

Key Molecule: Cancer susceptibility 11 (CASC11) [436]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Key Molecule: hsa-mir-27a [437]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Key Molecule: hsa-miR-210-3p [438]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR 210 3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

Key Molecule: hsa-mir-128a [439]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: Long non-protein coding RNA 161 (LINC00161) [439]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: hsa-mir-503 [440]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR503 might be a sensitizer to cisplatin treatment in ovarian cancer by targeting PI3k p85 and participating in the regulation of the PI3k/Akt signaling pathway. The role of miR503 in regulating cisplatin sensitivity in ovarian cancer cells is correlated with the activation of PI3k/Akt signaling.

Key Molecule: hsa-mir-21 [441]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN.

Key Molecule: hsa-miR-199a-3p [442]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR199a/DDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: IOSE386 cells; Ovary; Homo sapiens (Human); CVCL_E230
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Wound healing assay
• Mechanism Description: Suppressing miR199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. Overexpression of miR199a-3p significantly impaired the migratory, invasive, and tumorigenic capabilities of ovarian cancer cells as well as enhanced cisplatin resistance through inhibiting DDR1 expression.

Key Molecule: hsa-miR-509-3p [443]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: hsa-mir-137 [444]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: c-Myc signaling pathway; Activation; hsa05230
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: In resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin.

Key Molecule: hsa-mir-216a [445]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-216a increases cisplatin resistance in ovarian cancer cells via downregulating PTEN.

Key Molecule: hsa-miR-149-5p [446]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [104]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Owing to the aberrant methylation engendered by DNMT1 over-expression, miR-30a-5p, and miR-30c-5p levels dropped significantly in cisplatin-resistant ovarian cancer (OC) cells. On the contrary, miR-30a/c-5p inhibited Snail and DNMT1 directly. Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [104]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Owing to the aberrant methylation engendered by DNMT1 over-expression, miR-30a-5p, and miR-30c-5p levels dropped significantly in cisplatin-resistant ovarian cancer (OC) cells. On the contrary, miR-30a/c-5p inhibited Snail and DNMT1 directly. Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC.

Key Molecule: hsa-mir-130a [44], [447]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR130a/XIAP signaling pathway; Regulation; hsa05206
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-130a could suppress XIAP expression and sensitize A2780/DDP cells to cisplatin. And finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) []

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that EZH2 was overexpressed in cisplatin-resistant ovarian cancer cells compared with cisplatin-sensitive cells. Knockdown of EZH2 by RNA interference (RNAi) resensitized drug-resistant ovarian cancer A2780/DDP cells to cisplatin and decreased the level of H3K27 trimethylation (H3K27me3).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [418]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: ATP-binding cassette sub-family C5 (ABCC5) [420]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [414]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Zinc finger protein SNAI1 (SNAI1) [448]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells.

Key Molecule: hsa-mir-363 [448]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: General transcription and DNA repair factor IIH helicase subunit XPD (ERCC2) [416]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• Experiment for Molecule Alteration: CASP comet analysis
• Experiment for Drug Resistance: Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting and reducing the level of ERCC2.

Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutamate--cysteine ligase catalytic subunit (GCLC) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutamate--cysteine ligase regulatory subunit (GCLM) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutathione reductase (GSR) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Quinone reductase 1 (NQO1) [413]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Caspase-3 (CASP3) [417]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4) [417]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Transforming growth factor beta 1 (TGFB1) [417]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Phosphatase and tensin homolog (PTEN) [418]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: Neuron navigator 3 (NAV3) [419]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Several miRNAs that are increased in cisplatin-resistant cells. We show that most of these do not directly contribute to cisplatin resistance. Interestingly, miR-21-3p, the passenger strand of the known oncomiR, directed increased resistance to cisplatin in a range of ovarian cell lines. This effect was specific to the star strand, as miR-21-5p had the opposite effect and actually increased sensitivity of A2780 cells to cisplatin. We identify NAV3 as a potential target of miR-21-3p and show that knockdown of NAV3 increases resistance.

Key Molecule: Polycomb complex protein BMI-1 (BMI1) [420]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: Protein kinase C delta type (PRKCD) [421]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian papillary serous carcinoma [ICD-11: 2C73.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PRKCD signaling pathway; Inhibition; hsa05208
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: PRkCD, known as protein kinase C deta, is a PkC isozyme that acts as a substrate for caspase-3. Its activity is believed to be required for apoptosis induced by DNA damaging agents such as cisplatin, mitomycin C and doxorubicin. miR-224-5p could negatively regulate the expression of PRkCD, and together with PRkCD, they can serve as novel predictors and prognostic biomarkers for OPSC patient response to overall disease-specific survival. The PRkCD pathway may be a molecular mechanism through which miR-224-5p exerts its functions as an oncogene and enhancer of chemoresistance to cisplatin in OPSC patients.

Key Molecule: Programmed cell death protein 4 (PDCD4) [422]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk1/c-Jun pathway; Activation; hsa04010
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vitro Model: A2780CP20 cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Alamar blue dye assay
• Mechanism Description: Blocking the JNk-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNk-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.

Key Molecule: RAC-gamma serine/threonine-protein kinase (AKT3) [423]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 overexpression results in an inhibition of SkOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SkOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SkOV3, OVCAR3, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression.

Key Molecule: Protein jagged-1 (JAG1) [424]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JAG1/Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The forced expression of miR-199b-5p could suppress ovarian cancer cell growth and sensitize the cells to cisplatin-induced cytotoxicity. On the other hand, as a direct target of miR-199b-5p in ovarian cancer cells, JAG1 depletion by siRNAs also resulted in cell growth retardation and sensitization to cisplatin-induced cytotoxicity. In contrast, activating Notch1 signaling by JAG1 or repressing miR-199b-5p by anti-miR-199b-5p could induce the activity of JAG1-Notch1 signaling in ovarian cancer cells. The loss of miR-199b-5p increased the activation of JAG1-Notch1 signaling, which in turn promoted ovarian cancer progression and acquired chemoresistance.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [427]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of miR-106a dramatically decreased antiproliferative effects and apoptosis in-duced by cisplatin in A2780 cells, while overexpression of miR-106a significantly increased antiprolif-erative effects and apoptosis induced by cisplatin in A2780/DDP cells. Furthermore, miR-106a inhibited cell survival and cisplatin resistance through downregulating the expression of Mcl-1. Mcl-1 was a di-rect target of miR-106a.

Key Molecule: Collagen alpha-1(I) chain (COL1A1) [428]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: Kelch-like ECH-associated protein 1 (KEAP1) [430]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780 DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-141 regulates the expression of kEAP1 and that the repression of kEAP1 contributes to cisplatin resistance. Inhibition of NF-kB signaling enhances miR-141-mediated cisplatin sensitivity.

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [433]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bak1 was a direct target of miR-125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. miR-125b has a sig-nificantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression.

Key Molecule: Activin receptor-like kinase 7 (ALK7) [434]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Nodal/ALK7 signaling pathway; Inhibition; hsa04350
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: We found that miR-376c increased cell proliferation and survival, as well as spheroid formation, in part by targeting ALk7. We have also provided evidence that the Nodal-ALk7 pathway is involved in cisplatin-induced ovarian cancer cell death and that miR-376c might promote chemoresistance.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [44]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [23]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vitro Model: OVCA3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: OVCA633 cells; Ovary; Homo sapiens (Human); CVCL_W776
• In Vitro Model: OVCA680 cells; Ovary; Homo sapiens (Human); CVCL_W781
• In Vitro Model: OVCA702 cells; Ovary; Homo sapiens (Human); CVCL_W782
• In Vitro Model: OVCA810 cells; Ovary; Homo sapiens (Human); CVCL_W783
• Experiment for Molecule Alteration: Combined immunostaining and chromosome painting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: One possible down-stream candidate is XIAP, which is the most potent direct inhibitor of caspases and apoptosis among all human IAP family proteins. Down-regulated expression of XIAP has been shown to induce apoptosis in chemoresistant human ovarian cancer cells. Down-regulation of XIST might increase the expression level of XIAP and block drug-induced apoptosis to cause resistance phenotype.

Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2) [449]

• Molecule Alteration: Missense mutation; p.Y663C
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Retinoblastoma-associated protein (RB1) [449]

• Molecule Alteration: Missense mutation; p.E580X
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Retinoblastoma-associated protein (RB1) [449]

• Molecule Alteration: Missense mutation; p.E580X
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Matrix protein P1 (HSPD1) [450]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulations of PkM2 and HSPD1 involved in MDR in ovarian cancer.

Key Molecule: Pyruvate kinase M2 (PKM) [450]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulations of PkM2 and HSPD1 involved in MDR in ovarian cancer.

Key Molecule: Cullin-5 (CUL5) [437]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Dual luciferase assay; qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Key Molecule: Transcription factor E2F3 (E2F3) [438]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR 210 3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [439]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1) [440]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR503 might be a sensitizer to cisplatin treatment in ovarian cancer by targeting PI3k p85 and participating in the regulation of the PI3k/Akt signaling pathway. The role of miR503 in regulating cisplatin sensitivity in ovarian cancer cells is correlated with the activation of PI3k/Akt signaling.

Key Molecule: Phosphatase and tensin homolog (PTEN) [441]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN.

Key Molecule: Epithelial discoidin domain-containing receptor 1 (DDR1) [442]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR199a/DDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: IOSE386 cells; Ovary; Homo sapiens (Human); CVCL_E230
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay; Luciferase assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Wound healing assay
• Mechanism Description: Suppressing miR199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. Overexpression of miR199a-3p significantly impaired the migratory, invasive, and tumorigenic capabilities of ovarian cancer cells as well as enhanced cisplatin resistance through inhibiting DDR1 expression.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [443]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Regulation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: Protein wntless homolog (WLS) [443]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Regulation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [444]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: c-Myc/miR137/EZH2 signaling pathway; Regulation; hsa05206
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: In resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin.

Key Molecule: Phosphatase and tensin homolog (PTEN) [445]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-216a increases cisplatin resistance in ovarian cancer cells via downregulating PTEN.

Key Molecule: Serine/threonine-protein kinase 4 (MST1) [446]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: Protein salvador homolog 1 (SAV1) [446]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: Pyruvate dehydrogenase kinase 2 (PDK2) [451]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian clear cell Carcinoma [ICD-11: 2C73.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: RMG5 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: RMG1 cells; Ovary; Homo sapiens (Human); CVCL_1662
• In Vivo Model: ICR/nu female mice model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blotting assay
• Experiment for Drug Resistance: WST-8 assay
• Mechanism Description: Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species.

Key Molecule: Programmed cell death protein 4 (PDCD4) [426], [425]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: A2780-CP cells; Ovary; Homo sapiens (Human); CVCL_H745
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-21 enhanced the sensitivity of ovarian cancer cells to cisplatin, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, downregulation of PDCD4 results in drug resistance via enhanced expression of c-IAP2 and MDR1. And the enhancement of miR-106a expression contributes to the generation of CDDP-resistant ovarian cancer cells, partly by targeting PDCD4. PDCD4 promoted CDDP-induced apoptosis mainly through the death receptor-mediated pathway.

Key Molecule: Phosphatase and tensin homolog (PTEN) [431], [432], [435]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT/PTEN/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: SkOV3/CIS cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-93, a new family member of PTEN regulator, blocks PTEN translation leading to activation of the AkT pathway and played an important role in regulating cisplatin chemosensitivity pathway in ovarian cancer.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [452]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: OVCAR4 cells; Ovary; Homo sapiens (Human); CVCL_1627
• In Vitro Model: CH1 cells; Abdomen; Homo sapiens (Human); CVCL_D177
• In Vitro Model: 41M cells; Ascites; Homo sapiens (Human); CVCL_4993
• In Vitro Model: PXN94 cells; Pelvis; Homo sapiens (Human); CVCL_4994
• In Vitro Model: HX62 cells; Esophagus; Homo sapiens (Human); CVCL_4995
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ATP cell viability assay
• Mechanism Description: CCND1 may induce cisplatin resistance both through cell cycle control and inhibition of cellular apoptosis pathways, which have been previously observed37 and supported by our CCND1 knockdown study. The role of CCND1 in cell cycle control is well documented. CCND1 accumulates in cells at middle and late G1 phase and stimulate G1 progression to S phase. The proportion of parental cells in G1/0 correlated with the cisplatin sensitivity, with 833K cells having the highest G1/0 population cells and lowest EC50 value and GCT27 the lowest G1/0 population but highest EC50 score.

Key Molecule: GSK3B interacting protein (GSKIP) [414]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [453]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-595 [454]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: FTE187 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HG-SOC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HO8910PM cells; Ovary; Homo sapiens (Human); CVCL_0310
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1. The expression level of ABCB1 was inversely correlated with miR595 in the ovarian cancer tissues, overexpression of ABCB1 decreased the miR595-overexpressing HO8910PM and SkOV-3 cell sensitivity to cisplatin.

Key Molecule: hsa-mir-551b [455]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [413]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: H19 overexpression contributes to cisplatin resistance.

Key Molecule: hsa-mir-30a [456]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; Transwell assay
• Mechanism Description: Overexpression of miR-30a decreases cellular vitality, invasion, plasticity and EMT. ETAR is identified as a direct target of miR-30a, and their expression is inversely correlated in EOC cell lines and human tissue samples. Upregulation of miR-30a re-sensitizes resistant EOC cells to cisplatinum by binding ETAR. Overexpression of miR-30a inhibits tumor growth in cisplatinum-resistant xenografts.

Key Molecule: hsa-mir-186 [457]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. miR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells. miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-Pi.

Key Molecule: hsa-mir-100 [458]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression of miR-100 is downregulated in SkOV3/DDP cells. Overexpressing miR-100 may effectively increase the sensitivity to cisplatin of human ovarian epithelial cancer SkOV3/DDP cells and may reverse cisplatin-resistance of EOC (epithelial ovarian cancer).

Key Molecule: hsa-miR-634 [459]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: hsa-miR-133b [453]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Key Molecule: hsa-mir-506 [460]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.

Key Molecule: hsa-mir-93 [461]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: There is an elevated expression of DNA polymerase Eta (Pol Eta) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically (+) translesion DNA synthesis (TLS). Down-regulation of Pol Eta blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol Eta-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol Eta expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically (+) Pol Eta-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol Eta, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

Key Molecule: hsa-miR-449a [462]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-8 dye assay; Flow cytometry assay
• Mechanism Description: miR-449a was involved in cisplatin resistance and the overexpression of miR449a increased cisplatin sensitivity mainly through inhibiting proliferation and promoting apoptosis and the direct downregulating the expression of NOTCH1.

Key Molecule: hsa-mir-370 [463]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Endometrioid ovarian cancer [ICD-11: 2C73.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: TOV112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• Experiment for Molecule Alteration: qRT-PCR; Northern blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-370 (miR-370) was down-regulated in endometrioid ovarian cancer cells. In IGROV1 and TOV112D endometrioid ovarian cancer cells, miR-370 suppressed cellular viability and colony formation. miR-370 also (+) endometrioid ovarian cancer cell chemosensitivity to cDDP. Endoglin (ENG) was directly and negatively regulated by miR-370.

Key Molecule: hsa-mir-29b [464]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Key Molecule: hsa-mir-9 [465]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Homologous-recombination; Regulation
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor onset measured
• Mechanism Description: miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells, miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer, improve chemotherapeutic (like cisplatin) efficacy by increasing the sensitivity of cancer cells to DNA damage.

Key Molecule: hsa-mir-103 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-mir-152 [346]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: hsa-mir-185 [346]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: hsa-mir-199a [466]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Key Molecule: hsa-mir-130b [467]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. miR-130b modulates MDR by targeting CSF-1, Down-regulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3'-UTR of CSF-1.

Key Molecule: hsa-miR-509-3p [468]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT and DAPI assays
• Mechanism Description: miR509-3p could sensitize ovarian cancer cells to cisplatin treatment by targeting multiple anti-apoptosis genes including BCL2 and promoteing apoptosis in cancer cells.

Key Molecule: hsa-mir-708 [469]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF2BP1/AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity assay
• Mechanism Description: miR708 increases the susceptibility of ovarian cancer cells to cisplatin by targeting IGF2BP1 and inhibiting Akt signaling. miR708 downregulated the expression of IGF2BP1 and suppressed Akt phosphorylation. Silencing of IGF2BP1 markedly blocked the phosphorylation of Akt.

Key Molecule: hsa-miR-146a-5p [470]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual-luciferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: hsa-miR-490-3p [471]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR490-3p sensitizes ovarian cancer cells to cisplatin by directly targeting ABCC2. miR490-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ABCC2 expression.

Key Molecule: hsa-mir-216b [472]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay; CCK8 assay
• Mechanism Description: miR216b increases cisplatin sensitivity in ovarian cancer cells by targeting PARP1.

Key Molecule: hsa-miR-30a-5p [473]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: hsa-miR-30c-5p [473]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: hsa-mir-200b [474]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: hsa-mir-200c [474]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: hsa-miR-142-5p [475]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-142-5p decreases cisplatin IC50 in OVCAR3 and SkOV3 ovarian cancer cells via downregulating XIAP.

Key Molecule: hsa-miR-378a-3p [476]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-378a-3p sensitizes ovarian cancer cells to cisplatin through downregulating MAPk1/GRB2.

Key Molecule: hsa-mir-514 [477]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: hsa-mir-139 [478]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: hsa-mir-34 [479]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Soft agar colony formation assay
• Mechanism Description: miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.

Key Molecule: hsa-miR-199a-3p [480]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-199a-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ITGB8 expression.

Key Molecule: hsa-miR-139-5p [481], [482]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: c-Jun/BCL-xl signaling pathway; Regulation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer. And miR-139-5p overexpression combined with inactivation of the MAPk signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2.

Key Molecule: hsa-mir-23a [483], [484]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Inhibition of miR-23a expression increases the sensitivity of A2780 cells to cisplatin possibly by inhibiting the negative regulation by miR-23a target genes that causes inhibition of P-gp protein expression.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [454]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: FTE187 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HG-SOC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HO8910PM cells; Ovary; Homo sapiens (Human); CVCL_0310
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase activity assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1. The expression level of ABCB1 was inversely correlated with miR595 in the ovarian cancer tissues, overexpression of ABCB1 decreased the miR595-overexpressing HO8910PM and SkOV-3 cell sensitivity to cisplatin.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [457]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. miR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells. miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-Pi.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [484]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The expression of miR-23a in drug-resistance ovarian cancer A2780 cell lines obviously increased; The expression of Runx3 gene could be inhibited by the combination of miR-23a and Runx3 3'UTR domain, which restricted the effect of Runx3 gene on the silence of MDR1 expression; The expression of P-gp in drug-resistance tumor cell was obviously up-regulated, therefore the resistance mechanism was achieved by the classic resistance mechanism; If the expression of miR-23a was inhibited, the regulatory effect decreased, and the expression level of Runx3 increased, and the silent effect of MDR1 expression by Runx3 improved. The expression of P-gp decreased, so the classic resistance mechanism was also inhibited to various degrees, and then the sensitivity of cisplatin to drug-resistance increased.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [453]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [471]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay; Western blot analysis; Immunohistochemical staining assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR490-3p sensitizes ovarian cancer cells to cisplatin by directly targeting ABCC2. miR490-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ABCC2 expression.

Key Molecule: ATP-binding cassette sub-family A1 (ABCA1) [477]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: ATP-binding cassette sub-family A10 (ABCA10) [477]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: ATP-binding cassette sub-family F2 (ABCF2) [477]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [485]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST-8 assay; Flow cytometry assay
• Mechanism Description: The knockdown of HOTAIR using siRNAs with transfection reagent suppressed cell proliferation, reduced the invasion ability of the cells and notably, it restored cisplatin sensitivity of the cisplatin resistant cells specifically by enhancing cisplatin induced cytotoxicity and apoptosis in SkOV 3CDDP/R cells. HOTAIR is required for the maintenance of stemness in cancer cells lines, involving EMT triggering.

Key Molecule: Maternally expressed 3 (MEG3) [486]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: MEG3 upregulation can decrease EVs mediated transfer of miR214 in ovarian cancer cells, thereby reducing drug resistance.

Key Molecule: hsa-mir-214 [486]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: MEG3 upregulation can decrease EVs mediated transfer of miR214 in ovarian cancer cells, thereby reducing drug resistance.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [487]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1294 ameliorated cisplatin-resistant OC malignancy via inhibiting IGF1R.

Key Molecule: hsa-miR-1294 [487]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1294 ameliorated cisplatin-resistant OC malignancy via inhibiting IGF1R.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [455]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: E3 ubiquitin-protein ligase TRIM31 (TRIM31) [455]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: Endothelin-1 receptor (EDNRA) [456]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; Transwell assay
• Mechanism Description: Overexpression of miR-30a decreases cellular vitality, invasion, plasticity and EMT. ETAR is identified as a direct target of miR-30a, and their expression is inversely correlated in EOC cell lines and human tissue samples. Upregulation of miR-30a re-sensitizes resistant EOC cells to cisplatinum by binding ETAR. Overexpression of miR-30a inhibits tumor growth in cisplatinum-resistant xenografts.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [459]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [459]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [459]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Ribosomal protein S6 kinase alpha-3 (RPS6KA3) [459]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [460]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Homologous recombination-mediated repair pathway; Inhibition; hsa03440
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.

Key Molecule: DNA polymerase theta (POLQ) [461]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: There is an elevated expression of DNA polymerase Eta (Pol Eta) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically (+) translesion DNA synthesis (TLS). Down-regulation of Pol Eta blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol Eta-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol Eta expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically (+) Pol Eta-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol Eta, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

Key Molecule: Runt-related transcription factor 3 (RUNX3) [483]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Inhibition of miR-23a expression increases the sensitivity of A2780 cells to cisplatin possibly by inhibiting the negative regulation by miR-23a target genes that causes inhibition of P-gp protein expression.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [462]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-8 dye assay; Flow cytometry assay
• Mechanism Description: miR-449a was involved in cisplatin resistance and the overexpression of miR449a increased cisplatin sensitivity mainly through inhibiting proliferation and promoting apoptosis and the direct downregulating the expression of NOTCH1.

Key Molecule: Endoglin (ENG) [463]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Endometrioid ovarian cancer [ICD-11: 2C73.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: TOV112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-370 (miR-370) was down-regulated in endometrioid ovarian cancer cells. In IGROV1 and TOV112D endometrioid ovarian cancer cells, miR-370 suppressed cellular viability and colony formation. miR-370 also (+) endometrioid ovarian cancer cell chemosensitivity to cDDP. Endoglin (ENG) was directly and negatively regulated by miR-370.

Key Molecule: Autophagy-related protein 9A (ATG9A) [464]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [465]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Homologous-recombination; Regulation
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical staining assay
• Experiment for Drug Resistance: Tumor onset measured
• Mechanism Description: miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells, miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer, improve chemotherapeutic (like cisplatin) efficacy by increasing the sensitivity of cancer cells to DNA damage.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [346]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Chemoresistance; Inhibition; hsa05207
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: Extracellular matrix receptor III (CD44) [466]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [467]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. miR-130b modulates MDR by targeting CSF-1, Down-regulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3'-UTR of CSF-1.

Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A) [488]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vitro Model: A2780/CP cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable alpha subunit of HIF-1, HIF-1alpha, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1alpha degradation but did not downregulate HIF-1alpha in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1alpha (HIF-1alpha detaODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1alpha or pharmacological promotion of HIF-1alpha degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [468]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT and DAPI assays
• Mechanism Description: miR509-3p could sensitize ovarian cancer cells to cisplatin treatment by targeting multiple anti-apoptosis genes including BCL2 and promoteing apoptosis in cancer cells.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [469]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF2BP1/AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity assay
• Mechanism Description: miR708 increases the susceptibility of ovarian cancer cells to cisplatin by targeting IGF2BP1 and inhibiting Akt signaling. miR708 downregulated the expression of IGF2BP1 and suppressed Akt phosphorylation. Silencing of IGF2BP1 markedly blocked the phosphorylation of Akt.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [470]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [470]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [470]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [472]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; CCK8 assay
• Mechanism Description: miR216b increases cisplatin sensitivity in ovarian cancer cells by targeting PARP1.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [473]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: Zinc finger protein SNAI1 (SNAI1) [473]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [474]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [474]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: DNA (cytosine-5)-methyltransferase 3B (DNMT3B) [474]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [475]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-142-5p decreases cisplatin IC50 in OVCAR3 and SkOV3 ovarian cancer cells via downregulating XIAP.

Key Molecule: Transcription factor Jun (JUN) [482]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: c-Jun/BCL-xl signaling pathway; Regulation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [476]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-378a-3p sensitizes ovarian cancer cells to cisplatin through downregulating MAPk1/GRB2.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [476]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-378a-3p sensitizes ovarian cancer cells to cisplatin through downregulating MAPk1/GRB2.

Key Molecule: E3 ubiquitin-protein ligase RING2 (RING2) [481]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: Nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-139-5p overexpression combined with inactivation of the MAPk signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2.

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [478]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: Copper-transporting ATPase 2 (ATP7B) [478]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: Histone deacetylase 1 (HDAC1) [479]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Soft agar colony formation assay
• Mechanism Description: miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.

Key Molecule: Integrin beta-8 (ITGB8) [480]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-199a-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ITGB8 expression.

Endometrial cancer [ICD-11: 2C76]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200b [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: hsa-mir-200c [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: hsa-miR-429 [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [489]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Key Molecule: Multidrug resistance protein 3 (ABCB4) [489]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor AP2 alpha (TFAP2A) [32]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: Beclin-1 (BECN1) [489]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [489]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Key Molecule: hsa-mir-23b [490]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Endometrial carcinoma [ICD-11: 2C76.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEC1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: Human normal endometrial epithelial cell line; Uterus; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RNA pull-down assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Long non-coding RNA TUSC7 acted as a potential tumor suppressor gene to inhibit cell growth as well as advance the chemotherapy sensitivity through targeted silencing of miR23b.

Key Molecule: Tumor suppressor candidate 7 (TUSC7) [490]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Endometrial carcinoma [ICD-11: 2C76.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEC1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: Human normal endometrial epithelial cell line; Uterus; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Long non-coding RNA TUSC7 acted as a potential tumor suppressor gene to inhibit cell growth as well as advance the chemotherapy sensitivity through targeted silencing of miR23b.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein (MDR) [489]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [489]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin-1 (BECN1) [489]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Endometrial cancer [ICD-11: 2C76.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dual-color autophagy reporter assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: HOTAIR can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by increasing Beclin-1, MDR, and P-gp expression.

Cervical cancer [ICD-11: 2C77]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [491]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical squamous cell carcinoma [ICD-11: 2C77.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: ME-180 cells; Uterus; Homo sapiens (Human); CVCL_1401
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The down-regulation of PRkCD expression may be a molecular mechanism through which miR-181a exerts its functions as an oncogene and an enhancer of chemoresistance to cisplatin in cervical squamous cell carcinoma cells.

Key Molecule: hsa-mir-200b [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: hsa-mir-200c [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: hsa-miR-429 [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: hsa-let-7i [6]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reduced let-7i expression significantly increased the resistance of ovarian and breast cancer cells to the chemotherapy drug, cis-platinum.

Key Molecule: Growth arrest specific 5 (GAS5) [492]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Colony formation assay
• Mechanism Description: Down-regulation of LncRNA GAS5 strengthen cisplatin-induced apoptosis in cervical cancer by regulating STAT3 signaling via miR-21.

Key Molecule: hsa-mir-21 [492]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Colony formation assay
• Mechanism Description: Down-regulation of LncRNA GAS5 strengthen cisplatin-induced apoptosis in cervical cancer by regulating STAT3 signaling via miR-21.

Key Molecule: Cancer susceptibility 2 (CASC2) [493]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vitro Model: ME-180 cells; Uterus; Homo sapiens (Human); CVCL_1401
• In Vitro Model: H8 cells; Uterus; Homo sapiens (Human); CVCL_9389
• In Vitro Model: HCE1 cells; Uterus; Homo sapiens (Human); CVCL_A8SM
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CASC2 upregulated PTEN expression by direct inhibiting miR21 in the DDP-resistant cancer cells, leading to the down-regulation of p-AkT protein, CASC2 up-regulates PTEN as a ceRNA of miR21. Inhibiting miR21 increased the sensitivity of human glioblastoma cells U251 and LN229 to taxol.

Key Molecule: Growth arrest specific 5 (GAS5) [494]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The low level of GAS5 can down-regulate PTEN by interacting with miR21 because PTEN is one of the genes in the PI3k/Akt/mTOR pathway that can be regulated by GAS5 negatively. The low expression of PTEN activates the PI3k/Akt pathway.

Key Molecule: Urothelial cancer associated 1 (UCA1) [495]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: HeLa/DDP cells; Uterus; Homo sapiens (Human); CVCL_C869
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometric analysis
• Mechanism Description: Overexpression of UCA1 confers cisplatin resistance by promoting cancer cell proliferation, migration, and invasion and inhibiting apoptosis.

Key Molecule: hsa-miR-7-5p [496]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: There was a protective role of miR-7-5p in cervical cancer cells treated with cisplatin and that miR-7-5p expression.miR-7-5p reduced energy consumption via inhibiting PARP-1 expression, and miR-7-5p increased energy generation by suppressing the expression of Bcl-2.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [497]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: HOXD/AS1/miR130a-3p/ZEB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: HOXD-AS1 enhanced chemoresistance of cisplatin-resistant CC cells by modulating miR-130a-3p/ZEB1 axis expression.

Key Molecule: HOXD antisense growth-associated long non-coding RNA (HAGLR) [497]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: HOXD/AS1/miR130a-3p/ZEB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: HOXD-AS1 enhanced chemoresistance of cisplatin-resistant CC cells by modulating miR-130a-3p/ZEB1 axis expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein kinase C delta type (PRKCD) [491]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical squamous cell carcinoma [ICD-11: 2C77.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: ME-180 cells; Uterus; Homo sapiens (Human); CVCL_1401
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The down-regulation of PRkCD expression may be a molecular mechanism through which miR-181a exerts its functions as an oncogene and an enhancer of chemoresistance to cisplatin in cervical squamous cell carcinoma cells.

Key Molecule: Transcription factor AP2 alpha (TFAP2A) [32]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The transcription factor AP-2alpha functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2alpha, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2alpha gene and negatively regulated the expression of endogenous AP-2alpha proteins.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [492]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Colony formation assay
• Mechanism Description: Down-regulation of LncRNA GAS5 strengthen cisplatin-induced apoptosis in cervical cancer by regulating STAT3 signaling via miR-21.

Key Molecule: Phosphatase and tensin homolog (PTEN) [494]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The low level of GAS5 can down-regulate PTEN by interacting with miR21 because PTEN is one of the genes in the PI3k/Akt/mTOR pathway that can be regulated by GAS5 negatively. The low expression of PTEN activates the PI3k/Akt pathway.

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [494]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: GAS5 knockdown (SiHa/cDDP-GAS5-siRNA) and SiHa cells with miR21 overexpression (SiHa/cDDP-miR21) had an up-regulated level of pAkt.

Key Molecule: Caspase-3 (CASP3) [495]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: HeLa/DDP cells; Uterus; Homo sapiens (Human); CVCL_C869
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometric analysis
• Mechanism Description: UCA1 suppressed apoptosis by downregulating caspase 3 and upregulating CDk2, whereas enhanced cell proliferation by increased level of survivin and decreased level of p21.

Key Molecule: Cyclin-dependent kinase 2 (CDK2) [495]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: HeLa/DDP cells; Uterus; Homo sapiens (Human); CVCL_C869
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometric analysis
• Mechanism Description: UCA1 suppressed apoptosis by downregulating caspase 3 and upregulating CDk2, whereas enhanced cell proliferation by increased level of survivin and decreased level of p21.

Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [495]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: HeLa/DDP cells; Uterus; Homo sapiens (Human); CVCL_C869
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometric analysis
• Mechanism Description: UCA1 suppressed apoptosis by downregulating caspase 3 and upregulating CDk2, whereas enhanced cell proliferation by increased level of survivin and decreased level of p21.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [496]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: There was a protective role of miR-7-5p in cervical cancer cells treated with cisplatin and that miR-7-5p expression.miR-7-5p reduced energy consumption via inhibiting PARP-1 expression, and miR-7-5p increased energy generation by suppressing the expression of Bcl-2.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [496]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: There was a protective role of miR-7-5p in cervical cancer cells treated with cisplatin and that miR-7-5p expression.miR-7-5p reduced energy consumption via inhibiting PARP-1 expression, and miR-7-5p increased energy generation by suppressing the expression of Bcl-2.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-103 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [90]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-mir-218 [498]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Inhibition; hsa04150
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Overexpression of miR-218 Inhibited Expression of Rictor, an mTOR Component, and Its Downstream Pathway, inhibited the proliferation of the human cervical cancer cell line HeLa and increased chemosensitivity to cisplatin in vitro by blocking the AkT-mTOR signaling pathway.

Key Molecule: hsa-mir-214 [499]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-214 significantly reduced cell survival and rendered cell sensitivity to cisplatin through inhibiting the anti-apoptotic protein Bcl2l2.

Key Molecule: hsa-mir-96 [91]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: hsa-mir-30a [254]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: NCK1 divergent transcript (NCK1-DT) [500]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Silencing of NCk1-AS1 and upregulation of miR-134-5p promote HeLa cell apoptosis and reduce cisplatin resistance in cervical cancer cells.

Key Molecule: hsa-miR-134-5p [500]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Silencing of NCk1-AS1 and upregulation of miR-134-5p promote HeLa cell apoptosis and reduce cisplatin resistance in cervical cancer cells.

Key Molecule: Cancer susceptibility 2 (CASC2) [493]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN signaling pathway; Activation; hsa05235
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vitro Model: ME-180 cells; Uterus; Homo sapiens (Human); CVCL_1401
• In Vitro Model: H8 cells; Uterus; Homo sapiens (Human); CVCL_9389
• In Vitro Model: HCE1 cells; Uterus; Homo sapiens (Human); CVCL_A8SM
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CASC2 upregulated PTEN expression by direct inhibiting miR21 in the DDP-resistant cancer cells, leading to the down-regulation of p-AkT protein, CASC2 up-regulates PTEN as a ceRNA of miR21. Inhibiting miR21 increased the sensitivity of human glioblastoma cells U251 and LN229 to taxol.

Key Molecule: hsa-mir-21 [493]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN signaling pathway; Activation; hsa05235
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vitro Model: ME-180 cells; Uterus; Homo sapiens (Human); CVCL_1401
• In Vitro Model: H8 cells; Uterus; Homo sapiens (Human); CVCL_9389
• In Vitro Model: HCE1 cells; Uterus; Homo sapiens (Human); CVCL_A8SM
• Experiment for Molecule Alteration: qRT-PCR; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CASC2 upregulated PTEN expression by direct inhibiting miR21 in the DDP-resistant cancer cells, leading to the down-regulation of p-AkT protein, CASC2 up-regulates PTEN as a ceRNA of miR21. Inhibiting miR21 increased the sensitivity of human glioblastoma cells U251 and LN229 to taxol.

Key Molecule: hsa-miR-1284 [501]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• In Vitro Model: MS751 cells; Cervical; Homo sapiens (Human); CVCL_4996
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Transwell assay
• Mechanism Description: miR-1284 enhances sensitivity of cervical cancer cells to cisplatin via downregulating HMGB1.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-155 [502]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR155 reversed EGF-induced EMT by downregulating SMAD2 expression levels, and restraining cell growth by inhibiting CCND1 expression, increased the Chemo-sensitivity of Caski Cells to DDP.

Key Molecule: Mothers against decapentaplegic homolog 2 (SMAD2) [502]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR155 reversed EGF-induced EMT by downregulating SMAD2 expression levels, and restraining cell growth by inhibiting CCND1 expression, increased the Chemo-sensitivity of Caski Cells to DDP.

Key Molecule: Forkhead box protein M1 (FOXM1) [503]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• Experiment for Molecule Alteration: Immunohistochemistry; Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: Wound healing assay; Transwell invasion assay; MTT assay
• Mechanism Description: miR214 inhibits cell migration, invasion and promotes the drug sensitivity in human cervical cancer by targeting FOXM1. FOXM1 overexpression counteracts miR214 in cervical cancer, overexpression of FOXM1 reversed the inhibition in cell invasion caused by miR214 as well as the process of EMT, and neutralized the promotion of drug sensitivity to cisplatin that was induced by miR214.

Key Molecule: hsa-mir-214 [503]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Chemosensitivity; Activation; hsa05207
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Wound healing assay; Transwell invasion assay; MTT assay
• Mechanism Description: miR214 inhibits cell migration, invasion and promotes the drug sensitivity in human cervical cancer by targeting FOXM1. FOXM1 overexpression counteracts miR214 in cervical cancer, overexpression of FOXM1 reversed the inhibition in cell invasion caused by miR214 as well as the process of EMT, and neutralized the promotion of drug sensitivity to cisplatin that was induced by miR214.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Pvt1 oncogene (PVT1) [504]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: DoTc2 4510 cells; Cervix uteri; Homo sapiens (Human); CVCL_1181
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Transwell assay
• Mechanism Description: PVT1 knockdown by either siRNA or LNA oligonucleotides leads to increased responsiveness of SiHa cells to cisplatin.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: Rapamycin-insensitive companion of mTOR (RICTOR) [498]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Inhibition; hsa04150
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Overexpression of miR-218 Inhibited Expression of Rictor, an mTOR Component, and Its Downstream Pathway, inhibited the proliferation of the human cervical cancer cell line HeLa and increased chemosensitivity to cisplatin in vitro by blocking the AkT-mTOR signaling pathway.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [499]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-214 significantly reduced cell survival and rendered cell sensitivity to cisplatin through inhibiting the anti-apoptotic protein Bcl2l2.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [502]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR155 reversed EGF-induced EMT by downregulating SMAD2 expression levels, and restraining cell growth by inhibiting CCND1 expression, increased the Chemo-sensitivity of Caski Cells to DDP.

Key Molecule: Transcription factor 4 (TCF4) [502]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR155 reversed EGF-induced EMT by downregulating SMAD2 expression levels, and restraining cell growth by inhibiting CCND1 expression, increased the Chemo-sensitivity of Caski Cells to DDP.

Key Molecule: DNA repair protein REV1 (REV1) [91]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: Beclin-1 (BECN1) [254]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: Programmed cell death protein 4 (PDCD4) [492]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Colony formation assay
• Mechanism Description: Down-regulation of LncRNA GAS5 can suppress TIMP3 and PDCD4 expression by enhancing miR-21 expression to suppress apoptosis and promote migration, invasion and cisplatin resistance in cervical cancer through the STAT3 signaling pathway.

Key Molecule: Metalloproteinase inhibitor 3 (TIMP3) [492]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Colony formation assay
• Mechanism Description: Down-regulation of LncRNA GAS5 can suppress TIMP3 and PDCD4 expression by enhancing miR-21 expression to suppress apoptosis and promote migration, invasion and cisplatin resistance in cervical cancer through the STAT3 signaling pathway.

Key Molecule: DNA mismatch repair protein Msh2 (MSH2) [500]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: NCk1-AS1 downregulation and miR-134-5p upregulation suppress the expression of MSH2 and reduce cisplatin resistance in cervical cancer cells.

Key Molecule: Phosphatase and tensin homolog (PTEN) [493]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: Caski cells; Uterus; Homo sapiens (Human); CVCL_1100
• In Vitro Model: ME-180 cells; Uterus; Homo sapiens (Human); CVCL_1401
• In Vitro Model: H8 cells; Uterus; Homo sapiens (Human); CVCL_9389
• In Vitro Model: HCE1 cells; Uterus; Homo sapiens (Human); CVCL_A8SM
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CASC2 upregulated PTEN expression by direct inhibiting miR21 in the DDP-resistant cancer cells, leading to the down-regulation of p-AkT protein, CASC2 up-regulates PTEN as a ceRNA of miR21. Inhibiting miR21 increased the sensitivity of human glioblastoma cells U251 and LN229 to taxol.

Key Molecule: High mobility group protein B1 (HMGB1) [501]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• In Vitro Model: MS751 cells; Cervical; Homo sapiens (Human); CVCL_4996
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Transwell assay
• Mechanism Description: miR-1284 enhances sensitivity of cervical cancer cells to cisplatin via downregulating HMGB1.

Testicular cancer [ICD-11: 2C80]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-106b-5p [49]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Seminoma [ICD-11: 2C80.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: TCam-2 cells; Testicle; Homo sapiens (Human); CVCL_T012
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA-106b-5p in seminoma.

Key Molecule: hsa-miR-106b-5p [49]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Seminoma [ICD-11: 2C80.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: TCam-2 cells; Testicle; Homo sapiens (Human); CVCL_T012
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA-106b-5p in seminoma.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [49]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Seminoma [ICD-11: 2C80.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: TCam-2 cells; Testicle; Homo sapiens (Human); CVCL_T012
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA-106b-5p in seminoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Testis development-related protein 1 (TDRG1) [49]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Seminoma [ICD-11: 2C80.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: TCam-2 cells; Testicle; Homo sapiens (Human); CVCL_T012
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA-106b-5p in seminoma.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [452]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Testicular germ cell tumor [ICD-11: 2C80.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Susa cells; Thyroid gland; Homo sapiens (Human); CVCL_L280
• In Vitro Model: GCT27 cells; Thyroid gland; Homo sapiens (Human); CVCL_A344
• In Vitro Model: 833K cells; Abdomen; Homo sapiens (Human); CVCL_2292
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ATP cell viability assay
• Mechanism Description: CCND1 may induce cisplatin resistance both through cell cycle control and inhibition of cellular apoptosis pathways, which have been previously observed37 and supported by our CCND1 knockdown study. The role of CCND1 in cell cycle control is well documented. CCND1 accumulates in cells at middle and late G1 phase and stimulate G1 progression to S phase. The proportion of parental cells in G1/0 correlated with the cisplatin sensitivity, with 833K cells having the highest G1/0 population cells and lowest EC50 value and GCT27 the lowest G1/0 population but highest EC50 score.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-302a [505]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Testicular embryonal carcinoma [ICD-11: 2C80.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: NCCIT cells; Embryo; Homo sapiens (Human); CVCL_1451
• In Vitro Model: NT2 cells; Prostate; Homo sapiens (Human); CVCL_JA57
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-302a significantly increased the sensitivity of NT2 cells to cisplatin by enhancing cisplatin-induced G2/M phase arrest and the subsequent progression to apoptosis.

Prostate cancer [ICD-11: 2C82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-17-92 [506]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: hsa-mir-205 [46]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: hsa-mir-31 [46]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: hsa-mir-218 [507]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR218 inhibited cell viability, migration, and invasion in PC3 and DU145 cells. Overexpression of BCAT1 decreased the chemosensitivity to CDDP treatment of PC3 and DU145 cells. The tumor suppressive role of miR218 was mediated by negatively regulating BCAT1 protein expression.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [508]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: However, higher concentrations of probenecid (500 uM) failed to demonstrate a chemosensitizing effect. Consistent with this lower chemosensitizing efficacy in higher-concentration probenecid treatment, we observed that the expression of ABCG2, a drug-efflux transporter, increased in a dose-dependent manner following probenecid treatment. Thus, probenecid could enhance the chemosensitivity of 3D-cultured prostate cancer cells, but not at higher concentr.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [508]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: However, higher concentrations of probenecid (500 uM) failed to demonstrate a chemosensitizing effect. Consistent with this lower chemosensitizing efficacy in higher-concentration probenecid treatment, we observed that the expression of ABCG2, a drug-efflux transporter, increased in a dose-dependent manner following probenecid treatment. Thus, probenecid could enhance the chemosensitivity of 3D-cultured prostate cancer cells, but not at higher concentr.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [506]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: BH3-interacting domain death agonist (BID) [506]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Bcl-2-interacting killer (BIK) [506]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [506]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [46]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: Transcription factor E2F6 (E2F6) [46]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: Branched-chain-amino-acid aminotransferase (BCAT1) [507]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR218 inhibited cell viability, migration, and invasion in PC3 and DU145 cells. Overexpression of BCAT1 decreased the chemosensitivity to CDDP treatment of PC3 and DU145 cells. The tumor suppressive role of miR218 was mediated by negatively regulating BCAT1 protein expression.

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [26]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostatic intraepithelial neoplasia [ICD-11: 2C82.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCalpha concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance.

Key Molecule: Ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) [26]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostatic intraepithelial neoplasia [ICD-11: 2C82.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCalpha concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [452]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ATP cell viability assay
• Mechanism Description: CCND1 may induce cisplatin resistance both through cell cycle control and inhibition of cellular apoptosis pathways, which have been previously observed37 and supported by our CCND1 knockdown study. The role of CCND1 in cell cycle control is well documented. CCND1 accumulates in cells at middle and late G1 phase and stimulate G1 progression to S phase. The proportion of parental cells in G1/0 correlated with the cisplatin sensitivity, with 833K cells having the highest G1/0 population cells and lowest EC50 value and GCT27 the lowest G1/0 population but highest EC50 score.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-128a [509]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-128 binded to the 3'UTR of ZEB1 and inhibited its expression. And ZEB1 (+) PCa chemoresistance and invasion, while miR-128 could reverse that by down-regulated ZEB1. These indicated that miR-128-mediated sensitizing chemoresistance and inhibiting invasion of PCa cells by directly targeting ZEB1.

Key Molecule: hsa-mir-205 [510]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Lysosome disturbance caused by miR-205-mediated down-regulation of RAB27A and LAMP3 constraints the completion of the autophagic flux by compromising the maturation step and, consequently, interferes with the detoxifying capabilities by which PCa cells may become resistant to CDDP.

Key Molecule: hsa-mir-205 [511]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: UTMD mediated miR 205 transfection increased the expression of caspase 9, cleaved caspase 9, cytochrome c and E cadherin, and decreased the expression of MMP 9 and p ERk,inhibiting PCa cell proliferation, migration and invasion, and promoted apoptosis modulated by cisplatin.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Matrix metalloproteinase-9 (MMP9) [511]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: UTMD mediated miR 205 transfection increased the expression of caspase 9, cleaved caspase 9, cytochrome c and E cadherin, and decreased the expression of MMP 9 and p ERk,inhibiting PCa cell proliferation, migration and invasion, and promoted apoptosis modulated by cisplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [509]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-128 binded to the 3'UTR of ZEB1 and inhibited its expression. And ZEB1 (+) PCa chemoresistance and invasion, while miR-128 could reverse that by down-regulated ZEB1. These indicated that miR-128-mediated sensitizing chemoresistance and inhibiting invasion of PCa cells by directly targeting ZEB1.

Key Molecule: Lysosome-associated membrane glycoprotein 3 (LAMP3) [510]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Lysosome disturbance caused by miR-205-mediated down-regulation of RAB27A and LAMP3 constraints the completion of the autophagic flux by compromising the maturation step and, consequently, interferes with the detoxifying capabilities by which PCa cells may become resistant to CDDP.

Key Molecule: Ras-related protein Rab-27A (RAP27A) [510]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Lysosome disturbance caused by miR-205-mediated down-regulation of RAB27A and LAMP3 constraints the completion of the autophagic flux by compromising the maturation step and, consequently, interferes with the detoxifying capabilities by which PCa cells may become resistant to CDDP.

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: SET and MYND domain containing 2 (SMYD2) [13]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: SMYD2 is a histone methyltransferase.The estimated IC50 values of cisplatin, doxorubicin, or 5-FU (but not docetaxel) for AZ505-treated RCC cells were significantly lower than those for the control cells, indicating that the SMYD2 inhibition enhanced the drug sensitivity in renal cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27b [252]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: hsa-mir-148a [512]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Caspase signaling pathway; Activation; hsa04210
• In Vitro Model: Caki cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay; PI/Annexin staining assay
• Mechanism Description: miR148a increases the sensitivity to cisplatin by targeting Rab14 in renal cancer cells, transfection with the miR148a mimics resulted in the activation of caspase pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-G1 (CCNG1) [252]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: Ras-related protein Rab-14 (RAB14) [512]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Caspase signaling pathway; Activation; hsa04210
• In Vitro Model: Caki cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; PI/Annexin staining assay
• Mechanism Description: miR148a increases the sensitivity to cisplatin by targeting Rab14 in renal cancer cells, transfection with the miR148a mimics resulted in the activation of caspase pathway.

Ureteral cancer [ICD-11: 2C92]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-193b [513]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Urothelial carcinoma [ICD-11: 2C92.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NTUB1 cells; Bladder; Homo sapiens (Human); CVCL_RW29
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometer
• Mechanism Description: miR193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells. miR193b-3p, a known tumor suppressor, down-regulated proto-oncogenes Cyclin D1, and ETS1 expression and led to cell cycle arrest, cell invasion, and migration inhibition.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [513]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Urothelial carcinoma [ICD-11: 2C92.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NTUB1 cells; Bladder; Homo sapiens (Human); CVCL_RW29
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometer
• Mechanism Description: miR193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells. miR193b-3p, a known tumor suppressor, down-regulated proto-oncogenes Cyclin D1, and ETS1 expression and led to cell cycle arrest, cell invasion, and migration inhibition.

Key Molecule: Protein C-ets-1 (ETS1) [513]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Urothelial carcinoma [ICD-11: 2C92.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NTUB1 cells; Bladder; Homo sapiens (Human); CVCL_RW29
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometer
• Mechanism Description: miR193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells. miR193b-3p, a known tumor suppressor, down-regulated proto-oncogenes Cyclin D1, and ETS1 expression and led to cell cycle arrest, cell invasion, and migration inhibition.

Bladder cancer [ICD-11: 2C94]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-196a-5p [514]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR196a-5p in bladder cancer cells. UCA1 upregulates miR196a-5p through transcription factor CREB.

Key Molecule: Urothelial cancer associated 1 (UCA1) [515]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Urinary bladder cancer [ICD-11: 2C94.Z]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy results in up-regulation of UCA1 expression, UCA1 increases cell viability during cisplatin treatment, UCA1 activates Wnt signaling in a Wnt6-dependent manner, UCA1 promotes cisplatin resistance by up-regulating Wnt6 expression.

Key Molecule: Long non-protein coding RNA (UCA1a) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vitro Model: BLZ-211 cells; Bladder; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Moreover, microarray analysis demonstrated that overexpression of UCA1a(CUDR) was associated with signaling pathways regulating cell apoptosis and tumorigen-esis. Furthermore, overexpression of UCA1a(CUDR) could antagonize cell apoptosis induced by cisplatin and promote the tumorigenicity of UM-UC-2 cells in vivo.

Key Molecule: hsa-miR-34b-3p [516]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p represses the multidrug-chemoresistance (Paclitaxel; Pirarubicin; Epirubicin hydrochloride; Adriamycin; Cisplatin) of bladder cancer cells by regulating the CCND2 and P2RY1 genes.

Key Molecule: hsa-mir-98 [517]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Drp1 signaling pathway; Activation; hsa04668
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells through Drp1 signaling.

Key Molecule: HIF1A antisense RNA 3 (HIF1A-AS3) [518]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer.

Key Molecule: hsa-miR-22-3p [519]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [520]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression levels of miR34a were decreased and GOLPH3 were increased in GC chemoresistant UBC cell lines. Down-regulation of miR34a resulted in the overexpression of GOLPH3.The ectopic expression of miR34a decreased the stem cell properties of chemoresistant UBC cells and re-sensitized these cells to GC treatment in vitro and in vivo.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Interleukin-1 beta (IL1B) [29]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vivo Model: Balb/cA Jcl nu/nu nude mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Cell count assay
• Mechanism Description: Aldo-keto reductase 1C1 (AkR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. Antagonized AkR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. Metastatic tumor cells possess higher expression levels of endogenous IL-6 and IL-1beta and their receptors. IL-1beta enhanced the expression of AkR1C1 in the three bladder cancer cell lines, UM-UC-3, TCC-SUP, and 5637 cells. Inhibition of 17beta-estradiol by AkR1C1 may recover cell motility in cancer cells.

Key Molecule: Transcription factor SOX-2 (SOX2) [521]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: BFTC 909 cells; Kidney; Homo sapiens (Human); CVCL_1084
• In Vitro Model: BFTC 905 cells; Urinary bladder; Homo sapiens (Human); CVCL_1083
• In Vitro Model: HT-1376 cells; Urinary bladder; Homo sapiens (Human); CVCL_1292
• In Vitro Model: SCaBER cells; Urinary bladder; Homo sapiens (Human); CVCL_3599
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC3 cells; Urinary bladder; Homo sapiens (Human); CVCL_1783
• In Vivo Model: Athymic (nu+/nu+) mouse xenograft model; NOD/SCID/IL2Rgamma -/- mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: Chemotherapy-induced COX2 and YAP1 signaling may promote CSC expansion via SOX2 overexpression and subsequent chemotherapy resistance.The YAP1-SOX2 axis, via re-activated PI3K/AKT signaling, may also be relevant to an acquired resistance to the EGFR inhibitor, as demonstrated by our findings that the resistant tumors again became sensitive to the EGFR inhibitor in combination with the YAP1 inhibitor.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [514]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: miR196a-5p is involved in UCA1-mediated cisplatin/gemcitabine resistance via targeting p27kip1.

Key Molecule: Protein Wnt-6 (WNT6) [515]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Urinary bladder cancer [ICD-11: 2C94.Z]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy results in up-regulation of UCA1 expression, UCA1 increases cell viability during cisplatin treatment, UCA1 activates Wnt signaling in a Wnt6-dependent manner, UCA1 promotes cisplatin resistance by up-regulating Wnt6 expression.

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [516]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p represses the multidrug-chemoresistance (Paclitaxel; Pirarubicin; Epirubicin hydrochloride; Adriamycin; Cisplatin) of bladder cancer cells by regulating the CCND2 and P2RY1 genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [516]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p represses the multidrug-chemoresistance (Paclitaxel; Pirarubicin; Epirubicin hydrochloride; Adriamycin; Cisplatin) of bladder cancer cells by regulating the CCND2 and P2RY1 genes.

Key Molecule: Ceramide synthase 2 (CERS2) [517]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Drp1 signaling pathway; Activation; hsa04668
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells through Drp1 signaling.

Key Molecule: High mobility group protein HMG-I/HMG-Y (HMGA1) [518]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: HMGA1 contributes to Cis resistance in bladder cancer by hampering the transcription activity of p53 family proteins.

Key Molecule: Cellular tumor antigen p53 (TP53) [518]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer.

Key Molecule: Apoptosis regulator BAX (BAX) [518]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [519]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Urothelial cancer associated 1 (UCA1) [514]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR196a-5p in bladder cancer cells. UCA1 upregulates miR196a-5p through transcription factor CREB.

Key Molecule: hsa-miR-1182 [522]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: BCa cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: Hcv29 cells; Bladder; Homo sapiens (Human); CVCL_8228
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-1182 was significantly downregulated in bladder cancer cells and tumor tissues. miR-1182 inhibited cell proliferation and invasion, induced apoptosis and cell cycle arrest, and mediated the chemosensitivity of bladder cancer cells to cisplatin by targeting hTERT.

Key Molecule: hsa-mir-203 [523]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-203 could directly bind the 3'-UTR of both Bcl-w and Survivin, resulting in down-regulated expression of Bcl-w and Survivin at post-transcriptional level. miR-203 can be used as a predictor for progression and prognosis of BC patients treated with cisplatin based chemotherapy. Moreover, overexpression of miR-203 can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Key Molecule: hsa-miR-193a-3p [524]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Key Molecule: hsa-mir-150 [525]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via downretulating PDCD4.

Key Molecule: hsa-mir-101 [526]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by downregulating the cyclooxygenase-2 pathway.

Key Molecule: hsa-mir-27a [527]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: EJ/T24 cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Clonogenic survival assay
• Mechanism Description: Cisplatin resistance is mediated through increased expression of SLC7A11 and increased production of glutathione, Overexpression of microRNA 27a reduces levels of SLC7A11 and intracellular glutathione, and resensitises resistant cells to cisplatin, SLC7A11 is a key modulator of cisplatin resistance in bladder cancer cells.

Key Molecule: hsa-mir-34 [528]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Tumorigenicity in nude mice
• Mechanism Description: Cisplatin-based chemotherapy induced demethylation of miR-34a promoter and increased miR-34a expression, which in turn sensitized MIBC cells to cisplatin and decreased the tumorigenicity and proliferation of cancer cells that by reducing the production of CD44.

Key Molecule: hsa-mir-34 [529]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Cdk6, in complex with Cdk4 and cyclin D1, is a key regulator of Rb activity and thereby G1/S transition, SIRT-1 is a deacetylase whose targets including p53, FOXO, SFRP1 and PGC1. Transfection with pre-miR-34a increases chemo-sensitivity to cisplatin through inhibition of Cdk6 and SIRT-1.

Key Molecule: hsa-mir-214 [530]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT phosphorylation signaling pathway; Inhibition; hsa00190
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 214 reduces chemoresistance by targeting netrin 1 in bladder cancer cell lines and inhibits AkT phosphorylation.

Key Molecule: hsa-mir-218 [531]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR218-Glut1 signaling pathway; Regulation; hsa05206
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR218 increases the sensitivity of bladder cancer to cisplatin by targeting Glut1.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Cystine/glutamate transporter (SLC7A11) [527]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: EJ/T24 cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• Experiment for Molecule Alteration: Tissue array assay
• Experiment for Drug Resistance: Clonogenic survival assay
• Mechanism Description: Cisplatin resistance is mediated through increased expression of SLC7A11 and increased production of glutathione, Overexpression of microRNA 27a reduces levels of SLC7A11 and intracellular glutathione, and resensitises resistant cells to cisplatin, SLC7A11 is a key modulator of cisplatin resistance in bladder cancer cells.

Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [531]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR218-Glut1 signaling pathway; Regulation; hsa05206
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR218 increases the sensitivity of bladder cancer to cisplatin by targeting Glut1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Telomerase reverse transcriptase (TERT) [522]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: BCa cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: Hcv29 cells; Bladder; Homo sapiens (Human); CVCL_8228
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-1182 was significantly downregulated in bladder cancer cells and tumor tissues. miR-1182 inhibited cell proliferation and invasion, induced apoptosis and cell cycle arrest, and mediated the chemosensitivity of bladder cancer cells to cisplatin by targeting hTERT.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [523]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-203 could directly bind the 3'-UTR of both Bcl-w and Survivin, resulting in down-regulated expression of Bcl-w and Survivin at post-transcriptional level. miR-203 can be used as a predictor for progression and prognosis of BC patients treated with cisplatin based chemotherapy. Moreover, overexpression of miR-203 can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [523]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-203 could directly bind the 3'-UTR of both Bcl-w and Survivin, resulting in down-regulated expression of Bcl-w and Survivin at post-transcriptional level. miR-203 can be used as a predictor for progression and prognosis of BC patients treated with cisplatin based chemotherapy. Moreover, overexpression of miR-203 can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Key Molecule: Presenilin-1 (PSEN1) [524]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Key Molecule: Programmed cell death protein 4 (PDCD4) [525]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via downretulating PDCD4.

Key Molecule: Prostaglandin G/H synthase 2 (PTGS2) [526]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by downregulating the cyclooxygenase-2 pathway.

Key Molecule: Extracellular matrix receptor III (CD44) [528]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Tumorigenicity in nude mice
• Mechanism Description: Cisplatin-based chemotherapy induced demethylation of miR-34a promoter and increased miR-34a expression, which in turn sensitized MIBC cells to cisplatin and decreased the tumorigenicity and proliferation of cancer cells that by reducing the production of CD44.

Key Molecule: Cyclin-dependent kinase 6 (CDK6) [529]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Cdk6, in complex with Cdk4 and cyclin D1, is a key regulator of Rb activity and thereby G1/S transition, SIRT-1 is a deacetylase whose targets including p53, FOXO, SFRP1 and PGC1. Transfection with pre-miR-34a increases chemo-sensitivity to cisplatin through inhibition of Cdk6 and SIRT-1.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [529]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Cdk6, in complex with Cdk4 and cyclin D1, is a key regulator of Rb activity and thereby G1/S transition, SIRT-1 is a deacetylase whose targets including p53, FOXO, SFRP1 and PGC1. Transfection with pre-miR-34a increases chemo-sensitivity to cisplatin through inhibition of Cdk6 and SIRT-1.

Key Molecule: Netrin-1 (NTN1) [530]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT phosphorylation signaling pathway; Inhibition; hsa00190
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 214 reduces chemoresistance by targeting netrin 1 in bladder cancer cell lines and inhibits AkT phosphorylation.

Retina cancer [ICD-11: 2D02]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-3163 [532]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [532]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Beclin-1 (BECN1) [58]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-30d [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 8305C cells; Thyroid; Homo sapiens (Human); CVCL_1053
• In Vitro Model: SW1736 cells; Thyroid; Homo sapiens (Human); CVCL_3883
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-144 [533]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: ARO cells; Thyroid; Homo sapiens (Human); CVCL_0144
• In Vitro Model: HTori3 cell; Thyroid; Homo sapiens (Human); CVCL_4W02
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-144 could inhibit autophagy of ATC cells by down-regulating TGF-alpha, enhancing the cisplatin-sensitivity of ATC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protransforming growth factor alpha (TGFA) [533]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Anaplastic thyroid carcinoma [ICD-11: 2D10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: ARO cells; Thyroid; Homo sapiens (Human); CVCL_0144
• In Vitro Model: HTori3 cell; Thyroid; Homo sapiens (Human); CVCL_4W02
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-144 could inhibit autophagy of ATC cells by down-regulating TGF-alpha, enhancing the cisplatin-sensitivity of ATC cells.

Germ cell tumor [ICD-11: 2D12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HIC ZBTB transcriptional repressor 1 (HIC1) [10]

• Molecule Alteration: Methylation; Up-regulation
• Resistant Disease: Germ cell tumor [ICD-11: 2D12.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 833K-E cells; Ascites; Homo sapiens (Human); CVCL_2292
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: Promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin.

Key Molecule: Ras association domain-containing protein 1 (RASSF1) [10]

• Molecule Alteration: Methylation; Up-regulation
• Resistant Disease: Germ cell tumor [ICD-11: 2D12.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 833K-E cells; Ascites; Homo sapiens (Human); CVCL_2292
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: Promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin.

Head and neck cancer [ICD-11: 2D42]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Head and neck cancer [ICD-11: 2D42.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Exosomal miR-196a promotes cisplatin resistance in HNC cells through CDkN1B and ING5 downregulation.

Key Molecule: Growth protein 5 inhibitor (ING5) [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Head and neck cancer [ICD-11: 2D42.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Exosomal miR-196a promotes cisplatin resistance in HNC cells through CDkN1B and ING5 downregulation.

Key Molecule: hsa-mir-196a [11]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Head and neck cancer [ICD-11: 2D42.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SCC25 cells; Oral; Homo sapiens (Human); CVCL_1682
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SCC4 cells; Tongue; Homo sapiens (Human); CVCL_1684
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Exosomal miR-196a promotes cisplatin resistance in HNC cells through CDkN1B and ING5 downregulation.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-let-7d [534]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Clonogenic assay; MTT assay
• Mechanism Description: The level of let-7d expression is an important factor for cell response to irradiation and chemotherapeutics. Overexpressed let-7d inhibited chemoresistance to cisplatin and paclitaxel in OSCC-ALDH1+ cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [535]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Head and neck cancer [ICD-11: 2D42.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Inhibition; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell survival; Activation; hsa05200
• Cell Pathway Regulation: IL-1beta/IL-8/CXCR1 signaling pathway; Inhibition; hsa04060
• In Vitro Model: GNM cells; Oral; Homo sapiens (Human); CVCL_WL58
• In Vitro Model: SAS cells; Oral; Homo sapiens (Human); CVCL_1675
• In Vivo Model: BALB/c nude mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Oral cancer cells with sh-LINC00963 exhibited lower resistance to cisplatin or 5-FU compared to sh-Luc control. Moreover, the percentage and protein expression level of ABCB5 (ATP-binding cassette, subfamily B (MDR/TAP), member 5) was significantly reduced in both SAS and GNM cells with sh-LINC00963 knockdown. As an ATP-binding cassette transporter, ABCB5 has been known to act as a drug efflux transporter and confer multidrug resistance in diverse malign.

HPV-related cervical cancer [ICD-11: 2E67]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: HPV-related cervical cancer [ICD-11: 2E67.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: GSK3 pathway; Activation; hsa04340
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We examined the significance of HPV and HPV-driven pathways in CSCC pathogenesis and specially focused on its contribution to the neoplasm's severity, including its induction of rapid proliferation, survival, invasiveness, and chemoresistance. We hypothesized that the expression of the viral oncoproteins E6/E7, in addition to activation of the glycogen synthase kinase-3 (GSK3)alpha/beta signaling pathways, could influence the biology of CSCC. We used liquid N2 frozen/fresh human CSCC tissues and adjacent normal (AN) and chemoradiation-resistant CSCC to determine HPV16/18 E6 and HPV16 E7 and the expression and activation of the pERK1/2 and GSK3 pathways. Cisplatin-resistant cervical cancer cell lines, both HPV positive (HeLa and SiHa) and HPV negative (C33A), were created and used as a model to investigate cervical cancer invasion and resistance. We provide evidence that there is an increased dependence of GSK3beta signaling in HPV16/18-induced CSCC that promotes chemoresistance and invasiveness.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [91], [90]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: HPV-related endocervical adenocarcinoma [ICD-11: 2E67.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. And overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [214], [213]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: HPV-related endocervical adenocarcinoma [ICD-11: 2E67.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. And the antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Peripheral nerve sheath tumor [ICD-11: 2F3Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurofibromin (NF1) [24]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Peripheral nerve sheath tumor [ICD-11: 2F3Y.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: sNF02.2 cells; Lung; Homo sapiens (Human); CVCL_K280
• In Vitro Model: Hs 53.T cells; Skin; Homo sapiens (Human); CVCL_0786
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: Ez-Cytox assay
• Mechanism Description: High expression of Bcl-xL in the MPNST cells was caused by a decreased transcriptional expression of the NF1 gene. Down-regulation of the NF1 gene by RNA interference (RNAi) induced an increase in Bcl-xL expression and a decrease in its sensitivity to apoptosis in the benign neurofibroma cell line and primary normal cells.

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