Drug Information

Drug (ID: DG00300) and It's Reported Resistant Information

• Name: Oxaliplatin
• Synonyms: Eloxatin (TN); Medac (TN); Oxaliplatin (TN); Oxaliplatin (JAN/USAN/INN)
• Indication:
  In total 1 Indication(s)
  Colorectal cancer [ICD-11: 2B91]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (11 diseases)
  Colon cancer [ICD-11: 2B90]; [2]
  Colorectal cancer [ICD-11: 2B91]; [3]
  Esophageal cancer [ICD-11: 2B70]; [4]
  Esophageal squamous cell carcinoma [ICD-11: 2B70]; [5]
  Gastric cancer [ICD-11: 2B72]; [6]
  Liver cancer [ICD-11: 2C12]; [10]
  Neuroendocrine carcinoma [ICD-11: 2D4Y]; [13]
  Oesophagogastric cancer [ICD-11: 2B71]; [14]
  Oral squamous cell carcinoma [ICD-11: 2B6E]; [15]
  Ovarian cancer [ICD-11: 2C73]; [16]
  Pancreatic cancer [ICD-11: 2C10]; [17]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (12 diseases)
  Hepatocellular carcinoma [ICD-11: 2C12]; [8]
  Laryngeal carcinoma [ICD-11: 2C23]; [9]
  Melanoma [ICD-11: 2C30]; [12]
  Chronic myeloid leukemia [ICD-11: 2A20]; [18]
  Colon cancer [ICD-11: 2B90]; [19]
  Colorectal cancer [ICD-11: 2B91]; [20]
  Esophageal cancer [ICD-11: 2B70]; [14]
  Gastric cancer [ICD-11: 2B72]; [21]
  Liver cancer [ICD-11: 2C12]; [22]
  Pancreatic cancer [ICD-11: 2C10]; [17]
  Prostate cancer [ICD-11: 2C82]; [23]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [24]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Liver cancer [ICD-11: 2C12]; [11]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [1]
• Formula: C8H14N2O4Pt
• IsoSMILES: C1CC[C@H]([C@@H](C1)[NH-])[NH-].C(=O)(C(=O)O)O.[Pt+2]
• InChI: 1S/C6H12N2.C2H2O4.Pt/c7-5-3-1-2-4-6(5)8;3-1(4)2(5)6;/h5-8H,1-4H2;(H,3,4)(H,5,6);/q-2;;+2/t5-,6-;;/m1../s1
• InChIKey: DRMCATBEKSVAPL-BNTLRKBRSA-N
• PubChem CID: 9887053
• TTD Drug ID: D0Y3ME
• DrugBank ID: DB00526

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

  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

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [25]

• Sensitive Disease: Colorectal carcinoma [ICD-11: 2B91.3]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colorectal cancer [ICD-11: 2B91]
• The Specified Disease: Colorectal carcinoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.67E-06; Fold-change: -9.64E-02; Z-score: -4.72E+00
• Experimental Note: Identified from the Human Clinical Data
• 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: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-340 [68]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• 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: The ectopic overexpression of miR340 in CRC cell lines resulted in growth inhibition, apoptosis and enhanced chemosensitivity in vitro and in vivo, which was mediated by directly targeting RLIP76.

Key Molecule: hsa-mir-145 [69]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116/L-OHP cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR145 inhibits drug resistance to L-OHP of HCT116 cells through suppressing the expression of target gene GPR98.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: GIHCG inhibitor of miR-200b/200a/429 expression (GIHCG) [44]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• 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
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA GIHCG induces cancer progression and chemoresistance and indicates poor prognosis in colorectal cancer.

Key Molecule: piR-hsa-54265 [45]

• Resistant Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: piR-54265 binds PIWIL2 promotes CRC cell proliferation and invasiveness and 5-FU and oxaliplatin resistance via promoting oncogenic STAT3 signaling.

Key Molecule: hsa-let-7a [46]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• 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
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Transwell assays and wound healing assay; Flow cytometry assay
• Mechanism Description: ANRIL promotes chemoresistance via disturbing expression of ABCC1 by inhibiting the expression of Let-7a in colorectal cancer.

Key Molecule: hsa-mir-216b [47]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/PTEN/AKT signaling pathway; Regulation; N.A.
• 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: 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: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: CCD-18Co cells; Colon; Homo sapiens (Human); CVCL_2379
• In Vitro Model: COLO-678 cells; Colon; Homo sapiens (Human); CVCL_1129
• In Vitro Model: HT55 cells; Colon; Homo sapiens (Human); CVCL_1294
• In Vitro Model: LS1034 cells; Colon; Homo sapiens (Human); CVCL_1382
• In Vitro Model: SW1417 cells; Colon; Homo sapiens (Human); CVCL_1717
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vivo Model: BALB/c mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-216b promotes cell growth and enhances chemosensitivity of colorectal cancer by suppressing PDZ-binding kinase.

Key Molecule: hsa-mir-218 [48]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HCT-116/L-OHP cells; Kidney; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis of apoptosis
• Mechanism Description: Down-regulation of YEATS4 by miR218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy.

Key Molecule: Maternally expressed 3 (MEG3) [49]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.

Key Molecule: hsa-miR-625-3p [50]

• Resistant Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Molecule Alteration: Expression; Up-regulation
• 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: p38/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HEK293 Flp pFRT/eGFP cells; Kidney; Homo sapiens (Human); CVCL_U427
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Inactivation of MAP2k6-p38 signalling as one likely mechanism of oxaliplatin resistance, and miR-625-3p induces oxaliplatin resistance by abrogating MAP2k6-p38-regulated apoptosis and cell cycle control networks.

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

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53/miR520g/p21 signaling pathway; Regulation; N.A.
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: p53 suppresses miR-520g expression and that deletion of p53 up-regulates miR-520g expression. Inhibition of miR-520g in p53 / cells increased their sensitivity to 5-FU treatment. miR-520g conferred resistance to 5-FU-induced apoptosis through the inhibition of p21 expression, which is a direct target of miR-520g. Rescued expression of p21 in miR-520g-expressing colon cancer cells sensitized them to 5-FU-induced apoptosis. Importantly, experiments in tumor xenograft mouse models demonstrate that miR-520g reduced the effectiveness of 5-FU in the inhibition of tumor growth in vivo. Moreover, studies of colorectal cancer specimens indicate a positive correlation between miR-520g expression and chemoresistance.

Key Molecule: hsa-miR-17-5p [52]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• 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 migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT/PI3K signaling pathway; Activation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• 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 expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.

Key Molecule: hsa-mir-19a [53]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: Aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.

Key Molecule: hsa-mir-203 [20]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• 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: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3' untranslated region (3'UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-na ve CRC cells.

Key Molecule: hsa-mir-153 [3]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• 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-33b [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: MCRC patients; Homo sapiens
• Mechanism Description: The combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Key Molecule: hsa-miR-372 [54]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectal cancer cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: Colorectal cancer serum samples; Homo sapiens
• Experiment for Molecule Alteration: qRT-PCR; TaqMan low-density arrays
• Experiment for Drug Resistance: Detection of CA19-9 and CEA
• Mechanism Description: In this study, the expression levels of serum miRNAs in patients with CRC have been systematically determined and five serum miRNAs (miR-20a, miR-130, miR-145, miR-216 and miR-372) have been identified that are significantly upregulated in oxaliplatin-chemoresistant CRC patients compared with chemosensitive patients.

Key Molecule: hsa-miR-326 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR-326/NFIB axis; Regulation; N.A.
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Colorectal cancer tissue model; Nude mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR; Western blot; Dual-luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry; Transwell assay; Wound healing assay
• Mechanism Description: These data suggested that circ_0082182 elevated the NFIB expression to regulate OXA resistance and CRC progression by absorbing miR-326.

Key Molecule: hsa-miR-483 [5]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Apoptosis assay; CCK8 assay
• Mechanism Description: In this work, using small RNA sequencing (small RNA-Seq) and transcriptome sequencing (RNA-Seq), we found that down-regulated miR-483-3p was concurrent with up-regulated FAM171B in oxaliplatin-resistant colorectal cancer cell line HCT116/L as compared with its parental cell line HCT116

Key Molecule: hsa-miR-128-1 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• 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 Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: qPCR; Dual-luciferase reporter assay; Western blot
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: IRF-1 mediated long non-coding RNA PVT1-214 promotes oxaliplatin resistance of colorectal cancer via miR-128 inhibition

Key Molecule: hsa-miR-93 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: TGF-betasignalling pathway; Regulation; N.A.
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: The aim of this study was to analyze the effect of chemotherapy for mCRC on TGF-beta signaling and related miRNAs. Hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p were selected out of 316 miRNAs with multiple targets within the TGF-beta signaling by in silico analysis. SW620 cells were treated with chemotherapeutic drugs for mCRC for 1, 3 and 6 days and expression of selected miRNAs, PAI-1, CDH1 and VIM was measured. Expression of TGF-beta signaling-related hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p was time-dependently altered in SW620 cells treated with chemotherapeutics for mCRC. The expression of hsa-miR-93-5p remained downregulated after 6 days under combined treatments FOX and FIRI as well as the hsa-miR-17-5p expression under FIRI. Chemotherapy regimens for mCRC increased expression of a major TGF-beta signaling target gene PAI-1, independently of the selected miRNAs expression. These treatments also increased the expression of epithelial-mesenchymal transition (EMT) markers CDH1 and VIM on day 3 resulting in decrease of mesenchymal-like characteristics. However, their expression returned close to basal level on day 6. In conclusion, after initial response to chemotherapeutic drugs SW620 cells start to return close to the basal mesenchymal state while the long-term downregulated expression pattern of hsa-miR-93-5p and hsa-miR-17-5p makes them candidates worth testing as biomarkers for monitoring combined chemotherapeutic treatments therapy response in mCRC patients.

Key Molecule: hsa-miR-26b [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Furthermore, in OxPt-treated cells, hsa-miR-26b and hsa-miR-192 had three down-stream targets implying their important role in OxPt-resistance in HCT116, HT29 and LoVo cell lines.

Key Molecule: hsa-miR-155 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: On the other hand, hsa-miR-155 demonstrated a key role in Iri-resistance in all studied colon cancer cell lines through regulating the level of GPT2, NOB1 and KRCC1 (Fig. 6b).

Key Molecule: hsa-miR-335 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The hsa-miR-335 was found to have an indispensable role in downregulation of numerous DEGs. Consistent with this finding, overexpression of hsa-miR-335 in CRC and gastric cancer cells has been reported, previously [59, 60]. Yan et al. [59] stated that this miRNA participated in the regulation of some critical oncogenic signaling pathways including p53, Wnt, ErbB, MAPK, and TGF-beta, and its overexpression was associated with the high frequency recurrence and poor survival. More interestingly, hsa-miR-335 is located on chromosome 7, and LoVo cells possess trisomy of this chromosome [61]. This suggests a distinct function of this miRNA in acquired resistance of LoVo cells to chemotherapeutic drugs.

Key Molecule: hsa-miR-17 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signalling pathway; Regulation; N.A.
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: The aim of this study was to analyze the effect of chemotherapy for mCRC on TGF-beta signaling and related miRNAs. Hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p were selected out of 316 miRNAs with multiple targets within the TGF-beta signaling by in silico analysis. SW620 cells were treated with chemotherapeutic drugs for mCRC for 1, 3 and 6 days and expression of selected miRNAs, PAI-1, CDH1 and VIM was measured. Expression of TGF-beta signaling-related hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p was time-dependently altered in SW620 cells treated with chemotherapeutics for mCRC. The expression of hsa-miR-93-5p remained downregulated after 6 days under combined treatments FOX and FIRI as well as the hsa-miR-17-5p expression under FIRI. Chemotherapy regimens for mCRC increased expression of a major TGF-beta signaling target gene PAI-1, independently of the selected miRNAs expression. These treatments also increased the expression of epithelial-mesenchymal transition (EMT) markers CDH1 and VIM on day 3 resulting in decrease of mesenchymal-like characteristics. However, their expression returned close to basal level on day 6. In conclusion, after initial response to chemotherapeutic drugs SW620 cells start to return close to the basal mesenchymal state while the long-term downregulated expression pattern of hsa-miR-93-5p and hsa-miR-17-5p makes them candidates worth testing as biomarkers for monitoring combined chemotherapeutic treatments therapy response in mCRC patients.

Key Molecule: hsa-miR-199b [23]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SIRT1/CREB/KISS1 signaling pathway; Regulation; N.A.
• 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: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: Colorectal cancer patients; Nude mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: MiRNA microarray analysis; RT-qPCR; Western blot; Luciferase reporter assay
• Experiment for Drug Resistance: Tumor cell invasion assay; Wound healing assay; Cell chemosensitivity assay
• Mechanism Description: Downregulation of miR-199b is associated with distant metastasis in colorectal cancer via activation of SIRT1 and inhibition of CREB/KISS1 signaling

Key Molecule: hsa-miR-200b [55]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PRC2/SUZ12 pathway; Regulation; N.A.
• Cell Pathway Regulation: EMT pathway; Regulation; N.A.
• Cell Pathway Regulation: Wnt/beta-catenin pathway; Regulation; N.A.
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Immunocytochemistry; Western blot; RT-PCR
• Experiment for Drug Resistance: Clonogenic assay; Migration assay; Wound healing assay
• Mechanism Description: In our study, we show that downregulation of miR-200b/c and upregulation of SUZ12 leads to EMT in CRC.

Key Molecule: hsa-miR-221 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectal cancer cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: Colorectal cancer patients; Homo sapiens
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions.

Key Molecule: hsa-miR-31 [9]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FOXC1/miR31-5p/LATS2 pathway; Regulation; N.A.
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Microarray array analysis; Western blot; RT-qPCR; Luciferase Reporter Assay
• Experiment for Drug Resistance: MTT assay; TUNEL Assay
• Mechanism Description: Importantly, we reveal a novel drug-resistance mechanism in which the transcription factor FOXC1 binds to the miR-31 promoter to increase the expression of miR31-5p and regulate LATS2 expression, resulting in cancer cell resistance to OXA. These results suggest that miR-31-5p may be a novel biomarker involved in drug resistance progression in CRC patients. Moreover, the FOXC1/miR31-5p/LATS2 drug-resistance mechanism provides new treatment strategies for CRC in clinical trials.

Key Molecule: hsa-miR-20b [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR-20b-3p/DEPDC1 axis; Regulation; N.A.
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The binding of SIRT1 to miR-20b-3p promoter and the targeting relationship between miR-20b-3p and DEPDC1 were verified. An aberrant elevation in SIRT1 expression was seen in L-OHP-resistant CRC tissues and cells. Knockdown of SIRT1 sensitized CRC cells and xenografted CRC tumors to L-OHP. SIRT1 bound with miR-20b-3p promoter to regulate DEPDC1. Reducing miR-20b-3p or raising DEPDC1 levels weakened the effect of SIRT1 knockdown on L-OHP-resistant-CRC cells. SIRT1 enhances L-OHP resistance in CRC by mediating miR-20b-3p/DEPDC1 axis.

Key Molecule: SNHG5 [56]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: RT-qPCR
• Mechanism Description: Here, we identify and characterize SNHG5 as a stable cytoplasmic lncRNA with up-regulated expression in colorectal cancer. Depletion of SNHG5 induces cell cycle arrest and apoptosis in vitro and limits tumour outgrowth in vivo, whereas SNHG5 overexpression counteracts oxaliplatin-induced apoptosis.

Key Molecule: hsa-miR-1258 [57]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: MiRNAs differentially expressed in HCT116, HT29 and their oxaliplatin resistance cells. The results manifested has-miR-1258 down-regulated in the HCT116-OxR and HT29-OxR cells.

Key Molecule: LINC00467 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: We constructed a ceRNA network containing 503 lncRNA-miRNA-mRNA regulatory pairs, 210 lncRNA-miRNA pairs, 382 miRNA-mRNA pairs, and 212 mRNA co-expression pairs. The differentially expressed lncRNA, miRNA and mRNA were verified by qPCR. One lncRNA (HOTAIR) and 14 mRNAs significantly correlated with patient prognosis.

Key Molecule: hsa-miR-494 [58]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN/AKT pathway; Regulation; N.A.
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: MiR-494-3p expression in oxaliplatin-resistant HT-29 cells was much higher than that in parental HT-29 cells, accompanied by increased levels of MRP, P-gp, and AKT phosphorylation (p-AKT), and decreased phosphatase and tensin homolog (PTEN) (p < 0.001). The miR-494-3p mimic suppressed oxaliplatin-induced parental HT-29 cell apoptosis, while miR-494-3p inhibitor promoted oxaliplatin-resistant HT-29 cell apoptosis and decreased the levels of p-AKT, MRP and P-gp, while upregulating PTEN (p < 0.001). Furthermore, AKT inhibitor had similar effects as miR-494-3p inhibitor (p < 0.001). Experiments using nude mice demonstrated that inhibition of miR-494-3p accentuated the sensitivity of oxaliplatin-resistant HT-29 cells to oxaliplatin (p < 0.05).

Key Molecule: hsa-miR-1914 [59]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Plasma levels of miR-1914* and -1915 in chemoresistant CRC patients were different than levels in responders, and associated with clinical response. Overexpression of miR-1914* and -1915 in chemoresistant CRC cells reduced resistance to 5-FU and Oxaliplatin in vitro. The microRNAs suppressed chemoresistance in CRC tumors in mice by affecting cell growth, invasion, apoptosis and tumor suppressor function. miR-1914* and -1915 interacted with the 3'-untranslated region of NFIX and reduced NFIX its level in chemoresistant CRC cells. Overexpression of NFIX did not inhibit chemoresistant CRC cell motility and chemoresistant proteins when miR-1914* and -1915 were transfected.

Key Molecule: hsa-miR-625 [56]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Herein, we show that miR-625-3p functionally induces oxaliplatin resistance in CRC cells, and identify the signalling networks affected by miR-625-3p. We show that the p38 MAPK activator MAP2K6 is a direct target of miR-625-3p, and, accordingly, is downregulated in non-responder patients of oxaliplatin therapy. miR-625-3p-mediated resistance is reversed by anti-miR-625-3p treatment and ectopic expression of a miR-625-3p insensitive MAP2K6 variant. In addition, reduction of p38 signalling by using siRNAs, chemical inhibitors or expression of a dominant-negative MAP2K6 protein induces resistance to oxaliplatin. Transcriptome, proteome and phosphoproteome profiles confirm inactivation of MAP2K6-p38 signalling as one likely mechanism of oxaliplatin resistance. Our study shows that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p.

Key Molecule: hsa-miR-92a-1 [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-qPCR
• Mechanism Description: To investigate the potential mechanism of oxaliplatin resistance, the small-RNA-Sequence analyses and RNA-Sequence of HCT116 and HCT116-R cells were analyzed. The expression of hsa-mir-92a-1 is decreased.

Key Molecule: hsa-miR-27a [7]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We, therefore, asked whether miR-27a was able to influence the CRC treatment response. Our in silico analysis of the TCGA-COAD dataset revealed that miR-27a expression was higher in the CRCs resistant to therapy (i.e. with a stable or progressive disease).

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Aldolase B, fructose-bisphosphate (Aldolase B) [60]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: CRC patients; Homo Sapiens
• Experiment for Molecule Alteration: Immunohistochemical (IHC) staining
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 6-FU chemoresistance in CRC cells.

Key Molecule: Long intergenic non-protein coding RNA 1852 (LINC01852) [61]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis.

Key Molecule: Prostaglandin G/H synthase 2 (Cox-2) [62]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: our findings revealed that oxaliplatin impressed a specific lipid profile signature and lipid transcriptional reprogramming in HT29 cells, which provides new insights into biomarker discovery and pathways for overcoming drug resistance and adverse reactions.

Key Molecule: Inosine monophosphate dehydrogenase 2 (IMPDH2) [63]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Breast cancer; Activation; hsa05224
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• Cell Pathway Regulation: Adherens junction; Activation; hsa04520
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Long non-protein coding RNA (CCAL) [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line 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: 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: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA CCAL can be transferred from CAFs to cancer cells via exosomes, and exosome-enriched CCAL promoted Oxa and 5-FU chemoresistance of CRC cells.

Key Molecule: hsa-miR-1229-5p [64]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; N.A.
• 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: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: hsa-miR-1246 [64]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; N.A.
• 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: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: hsa-miR-21-5p [64]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; N.A.
• 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: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: hsa-miR-96-5p [64]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; N.A.
• 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: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: Phosphatase and tensin homolog (PTEN) [64]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; N.A.
• 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: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [65]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Boyden chambers cell migration and invasion assays
• Mechanism Description: MALAT1 tethers EZH2 to CDH1 promoter and suppresses miR218 during oxaliplatin treatment, which finally promotes colorectal cancer cell EMT, metastasis, and chemoresistance.

Key Molecule: Cadherin-1 (CDH1) [65]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Boyden chambers cell migration and invasion assays
• Mechanism Description: MALAT1 tethers EZH2 to CDH1 promoter and suppresses miR218 during oxaliplatin treatment, which finally promotes colorectal cancer cell EMT, metastasis, and chemoresistance.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [65]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Boyden chambers cell migration and invasion assays
• Mechanism Description: MALAT1 tethers EZH2 to CDH1 promoter and suppresses miR218 during oxaliplatin treatment, which finally promotes colorectal cancer cell EMT, metastasis, and chemoresistance. MALAT1 mediates oxaliplatin-induced EMT through EZH2 and interacts with miR218.

Key Molecule: hsa-mir-141 [66]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: CAF-derived exosomes transfer LncRNA H19 to colorectal cancer cells and H19 activated the beta-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [66]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Activation; hsa04520
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: NOD/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: CAF-derived exosomes transfer LncRNA H19 to colorectal cancer cells and H19 activated the beta-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Piwi-like protein 2 (PIWIL2) [45]

• Resistant Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• 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; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: piR-54265 binds PIWIL2 promotes CRC cell proliferation and invasiveness and 5-FU and oxaliplatin resistance via promoting oncogenic STAT3 signaling.

Key Molecule: T-LAK cell-originated protein kinase(PBK) [47]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/PTEN/AKT signaling pathway; Regulation; N.A.
• 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: 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: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: CCD-18Co cells; Colon; Homo sapiens (Human); CVCL_2379
• In Vitro Model: COLO-678 cells; Colon; Homo sapiens (Human); CVCL_1129
• In Vitro Model: HT55 cells; Colon; Homo sapiens (Human); CVCL_1294
• In Vitro Model: LS1034 cells; Colon; Homo sapiens (Human); CVCL_1382
• In Vitro Model: SW1417 cells; Colon; Homo sapiens (Human); CVCL_1717
• In Vitro Model: SW403 cells; Colon; Homo sapiens (Human); CVCL_0545
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vivo Model: BALB/c mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase activity assay; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-216b promotes cell growth and enhances chemosensitivity of colorectal cancer by suppressing PDZ-binding kinase.

Key Molecule: YEATS domain-containing protein 4 (YEATS4) [48]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HCT-116/L-OHP cells; Kidney; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis of apoptosis
• Mechanism Description: Down-regulation of YEATS4 by miR218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy.

Key Molecule: Programmed cell death protein 4 (PDCD4) [49]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay; RNA pull-down assay; RIP assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.

Key Molecule: MAPK/ERK kinase 6 (MEK6) [50]

• Resistant Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Molecule Alteration: Expression; Down-regulation
• 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: p38/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HEK293 Flp pFRT/eGFP cells; Kidney; Homo sapiens (Human); CVCL_U427
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Inactivation of MAP2k6-p38 signalling as one likely mechanism of oxaliplatin resistance, and miR-625-3p induces oxaliplatin resistance by abrogating MAP2k6-p38-regulated apoptosis and cell cycle control networks.

Key Molecule: Ribonuclease P protein subunit p21 (RPP21) [51]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53/miR520g/p21 signaling pathway; Regulation; N.A.
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: p53 suppresses miR-520g expression and that deletion of p53 up-regulates miR-520g expression. Inhibition of miR-520g in p53 / cells increased their sensitivity to 5-FU treatment. miR-520g conferred resistance to 5-FU-induced apoptosis through the inhibition of p21 expression, which is a direct target of miR-520g. Rescued expression of p21 in miR-520g-expressing colon cancer cells sensitized them to 5-FU-induced apoptosis. Importantly, experiments in tumor xenograft mouse models demonstrate that miR-520g reduced the effectiveness of 5-FU in the inhibition of tumor growth in vivo. Moreover, studies of colorectal cancer specimens indicate a positive correlation between miR-520g expression and chemoresistance.

Key Molecule: Phosphatase and tensin homolog (PTEN) [52]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• 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 migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT/PI3K signaling pathway; Activation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.

Key Molecule: Serine-protein kinase ATM (ATM) [20]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• 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: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3' untranslated region (3'UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-na ve CRC cells.

Key Molecule: Forkhead box protein O3 (FOXO3) [3]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• 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: Western blot 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: . [67]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/beta-catenin Signalling Pathway; Regulation; N.A.
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells.

Drug Sensitive Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-766 [7]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR-766-5p/TRIM67 axis; Regulation; N.A.
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: circ_0094343 was significantly downregulated in CRC tissues, chemotherapy-resistant CRC tissues, and metastatic CRC tissues. Moreover, exosomes-carried circ_0094343 played an inhibitory role in the proliferation, clone formation and glycolysis of HCT116ells. Meanwhile, it could also improve the chemosensitivity of HCT116 cells to 5-fluorouracil (5-FU), oxaliplatin (L-OHP), and doxorubicin (Dox). Additionally, circ_0094343 acted as a sponge for miR-766-5p, and miR-766-5p targeted and regulated TRIM67. In CRC tissues, miR-766-5p expression was negatively correlated with TRIM67 expression, while circ_0094343 was positively associated with TRIM67. Further, mechanistic validation also demonstrated that circ_0094343 could inhibit HCT116 cell proliferation, clone formation, glycolysis, and chemotherapy resistance via the miR-766-5p/TRIM67 axis.

Key Molecule: hsa-miR-338 [9]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/miR-338-5p/IL-6 Feedback Loop; Regulation; N.A.
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1 and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1 inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1/miR-338-5p/IL-6 feedback circuit that is critical in hypoxia-mediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC.

Key Molecule: hsa-miR-29c [8]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Colorectal cancer cells; Colon; Homo sapiens (Human); N.A.
• In Vivo Model: Colorectal cancer patients; Homo sapiens
• Experiment for Molecule Alteration: RT-PCR
• Mechanism Description: Specifically, significantly higher miR-29c-3p levels were observed in patients whose best response was disease control (response or stable disease) (p = .0051; Figure 4B).

Key Molecule: hsa-miR-15b [5]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Colorectal cancer patients; NOD SCID mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR; Luciferase Reporter Assay; Western blot
• Experiment for Drug Resistance: Cell Growth assays; Cell spreading assays; Motility assays; Invasion assays; Tumor growth and metastasis assay; Flow cytometry analysis; Spheroid formation assay; Cell cytotoxicity assay; Clonogenic survival assay
• Mechanism Description: Enhancement of Sensitivity to Chemo/Radiation Therapy by Using miR-15b against DCLK1 in Colorectal Cancer

Kidney cancer [ICD-11: 2C90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Metalloproteinase inhibitor 3 (TIMP3) [26]

• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal carcinoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.59E-02; Fold-change: 2.68E+00; Z-score: 3.16E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Key Molecule: Programmed cell death protein 4 (PDCD4) [26]

• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.62E-01; Fold-change: 6.66E-03; Z-score: 1.74E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD) [17]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Pancreatic cancer [ICD-11: 2C10]
• The Specified Disease: Pancreatic ductal adenocarcinoma
• The Studied Tissue: Pancreas
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.01E-17; Fold-change: 4.09E-01; Z-score: 9.54E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Mechanism Description: Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.

Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [17]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Pancreatic cancer [ICD-11: 2C10]
• The Specified Disease: Pancreatic ductal adenocarcinoma
• The Studied Tissue: Pancreas
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.33E-08; Fold-change: 5.47E-01; Z-score: 5.83E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Mechanism Description: Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.

Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [17]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Pancreatic cancer [ICD-11: 2C10]
• The Specified Disease: Pancreatic cancer
• The Studied Tissue: Pancreas
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.68E-16; Fold-change: 2.62E-01; Z-score: 1.07E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: Female SCID mice of 4-week-old, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.

Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD) [17]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Pancreatic cancer [ICD-11: 2C10]
• The Specified Disease: Pancreatic cancer
• The Studied Tissue: Pancreas
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.65E-04; Fold-change: 2.06E-01; Z-score: 4.69E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Adrenergic signaling in cardiomyocytes; Activation; hsa04261
• In Vivo Model: Female SCID mice of 6-week-old, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin receptor substrate 1 (IRS1) [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colon cancer [ICD-11: 2B90]
• The Specified Disease: Colon cancer
• The Studied Tissue: Colon tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.83E-01; Fold-change: -1.37E-01; Z-score: -1.08E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Regulation; N.A.
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Key Molecule: Ornithine decarboxylase antizyme 2 (OAZ2) [19]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colon cancer [ICD-11: 2B90]
• The Specified Disease: Colon cancer
• The Studied Tissue: Colon tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.25E-01; Fold-change: -1.09E-03; Z-score: -2.21E-01
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 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: WST-1 assay; Flow cytometry assay
• Mechanism Description: miR-34a positively regulates OAZ2 transcription by directly targeting its 3UTR and OAZ2 Overexpression Effectively Rescues the Chemosensitivity Impaired by miR-34a Deficiency.

Key Molecule: Target of Myb protein 1 (TOM1) [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colon cancer [ICD-11: 2B90]
• The Specified Disease: Colon cancer
• The Studied Tissue: Colon tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.36E-14; Fold-change: -4.30E-02; Z-score: -8.19E+00
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4) [30]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colon cancer [ICD-11: 2B90]
• The Specified Disease: Colon cancer
• The Studied Tissue: Colon tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.42E-04; Fold-change: -4.75E-02; Z-score: -3.85E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• 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: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.

Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4) [28]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• 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: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-APC/PI Apoptosis assay
• Mechanism Description: Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cytoskeleton regulator RNA (CYTOR) [28]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colon cancer [ICD-11: 2B90]
• The Specified Disease: Colon adenocarcinoma
• The Studied Tissue: Colon
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.65E-55; Fold-change: 1.61E+00; Z-score: 1.82E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• 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: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-APC/PI Apoptosis assay
• Mechanism Description: Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.

Key Molecule: hsa-miR-19b-3p [30]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• 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: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.

Key Molecule: hsa-mir-34 [19]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST-1 assay; Flow cytometry assay
• Mechanism Description: miR-34a positively regulates OAZ2 transcription by directly targeting its 3UTR and OAZ2 Overexpression Effectively Rescues the Chemosensitivity Impaired by miR-34a Deficiency.

Key Molecule: hsa-mir-126 [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

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

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: OAZ2 Signaling; Regulation; N.A.
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: RT-qPCR
• Mechanism Description: Here, we report for the first time that miR-34a expression was significantly downregulated in clinical CCa samples from oxaliplatin-resistant patients and in experimentally established multidrug-resistant CCa cells. By using histoculture drug response assay, we further confirmed that clinical CCa samples with lower miR-34a expression appeared to be more resistant to chemotherapy. Functionally, ectopic expression of exogenous miR-34a resensitized multidrug-resistant HCT-8/OR cells to oxaliplatin treatment, whereas miR-34a inhibition augmented the oxaliplatin resistance in chemosensitive HCT-8 cells. Mechanistically, miR-34a positively regulated the mRNA stability of the ornithine decarboxylase antizyme 2 (OAZ2) by directly targeting its three prime untranslated region (3'UTR). Consequently, suppression of the expression of miR-34a/OAZ2 signaling by chemotherapeutic agents significantly enhanced the activation of MDR-associated ATP-binding cassette (ABC) transporters and antiapoptosis pathways, thus leading to MDR development in CCa cells. Collectively, our combined analysis reveals a critical role of miR-34a/OAZ2 cascade in conferring a proper cellular response to CCa chemotherapy.

Key Molecule: hsa-miR-423 [7]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical analysis; qRT-PCR; Western blot; Fluorescence assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation experiment
• Mechanism Description: For hsa-miR-423-5p, PGM5-AS1 can also act as a sponge to upregulate the NME1 expression

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Solute carrier family 7 member 5 (SLC7A5) [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: POU class 2 homeobox 1 (POU2F1) [39]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• In Vitro Model: Patients cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer.

Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1) [18]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Expression profiles
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

Key Molecule: POU class 2 homeobox 1 (POU2F1) [39]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• In Vivo Model: Male BALB/c nude mice at 4-6 weeks, with SW620 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin-1 (BECN1) [31]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Colon cancer [ICD-11: 2B90]
• The Specified Disease: Colon cancer
• The Studied Tissue: Colon tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.40E-38; Fold-change: -6.21E-02; Z-score: -1.53E+01
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• 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 Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: CCD-18Co cells; Colon; Homo sapiens (Human); CVCL_2379
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR 409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR 409-3p (+) the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR 409-3p. In a xenograft model using nude mice, we examined the effects of miR 409-3p on tumor growth during chemotherapy. miR 409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1.

Key Molecule: Y-box-binding protein 1 (YBX1) [40]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-137 chemosensitizes colon cancer cells to the chemotherapeutic drug OXA by targeting YBX1, miR137 was involved in repression of YBX1 expression through targeting its 3'-untranslated region. Down-regulation of miR137 conferred OXA resistance in parental cells, while over-expression of miR137 sensitized resistant cells to OXA, which was partly rescued by YBX1 siRNA.

Key Molecule: Sal-like protein 4 (SALL4) [41]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• 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: 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: Forkhead box protein M1 (FOXM1) [42]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• 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
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-137 [40]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-137 chemosensitizes colon cancer cells to the chemotherapeutic drug OXA by targeting YBX1, miR137 was involved in repression of YBX1 expression through targeting its 3'-untranslated region. Down-regulation of miR137 conferred OXA resistance in parental cells, while over-expression of miR137 sensitized resistant cells to OXA, which was partly rescued by YBX1 siRNA.

Key Molecule: hsa-miR-409-3p [31]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• 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 Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: CCD-18Co cells; Colon; Homo sapiens (Human); CVCL_2379
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR 409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR 409-3p (+) the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR 409-3p. In a xenograft model using nude mice, we examined the effects of miR 409-3p on tumor growth during chemotherapy. miR 409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1.

Key Molecule: hsa-miR-219a-5p [41]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• 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: 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: hsa-mir-320 [42]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• 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
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Key Molecule: hsa-miR-320a [43]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR-320-FOXM1; Regulation; N.A.
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: qRT-PCR; Western blot; Luciferase assays
• Experiment for Drug Resistance: MTT assay; Colony formation assays; Apoptosis and cell cycle analysis; Migration and invasion assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1

Drug Sensitive Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-324 [7]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: TNF-alpha signalling pathway; Regulation; N.A.
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• 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: RT-PCR; Fluorescence in situ hybridization analysis; Western blot; Luciferase reporter assay; Coimmunoprecipitation
• Experiment for Drug Resistance: Flow cytometry; Transwell assay
• Mechanism Description: In conclusion, hsa_circ_0079662, as a ceRNA binding with hsa-mir-324-5p, can regulate target gene HOXA9 and induced the mechanism of chemotherapy drug oxaliplatin resistance in CRC through the TNF-alpha pathway in human colon cancer.

Liver cancer [ICD-11: 2C12]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [27]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.18E-05; Fold-change: -3.05E-01; Z-score: -4.26E+00
• 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/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• 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: MTT assay; Flow cytometry assay
• Mechanism Description: miR-122 inhibits MDR1 expression via suppression of Wnt/beta-catenin pathway, thereby enhancing HCC sensitivity to OXA.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22) [22]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.48E-08; Fold-change: 3.19E-01; Z-score: 5.81E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) [10]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Cholangiocarcinoma
• The Studied Tissue: Bile duct
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.01E-06; Fold-change: 2.31E+00; Z-score: 5.87E+00
• 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: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR7-5p/ABCC1 signaling pathway; Regulation; N.A.
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.

Key Molecule: NR2F1 antisense RNA 1 (NR2F1-AS1) [29]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Liver hepatocellular carcinoma
• The Studied Tissue: Liver
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.95E-01; Fold-change: 1.56E-01; Z-score: 1.30E+00
• 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: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: NR2F1/AS1/miR363/ABCC1 signaling pathway; Regulation; N.A.
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: Both NR2F1-AS1 and ABCC1 were up-regulated in oxaliplatin-resistant HCC cells,and miR-363 expression was increased in Huh7/OXA and HepG2/OXA cells transfected with NR2F1-AS1 siRNA compared to empty vector-transfected cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [10]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Liver cancer
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.12E-23; Fold-change: 1.52E-01; Z-score: 1.09E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR7-5p/ABCC1 signaling pathway; Regulation; N.A.
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.

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) [24]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Expression; Down-regulation
• 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) [24]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Expression; Up-regulation
• 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.

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1) [18]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD-1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/OxR cells; Blood; Homo sapiens (Human); CVCL_0248
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Expression profiles
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [15]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Molecule Alteration: Lactylation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: OSCC samples; Homo Sapiens
• Mechanism Description: We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC.

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-141-3p [4]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: EC9706-R cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: Het-1A cells; Esophagus; Homo sapiens (Human); CVCL_3702
• 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 Detection assay
• Mechanism Description: Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via down-regulation of PTEN.

Key Molecule: hsa-miR-1323 [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: RT-qPCR
• Mechanism Description: The miRNA profiles within and between non-responders and responders were highly similar (r = 0.96, 0.94 and 0.95). However, 12 miRNAs were differentially expressed (> twofold; p <= 0.025): non-responders showed upregulation of hsa-miR-1323, hsa-miR-3678-3p, hsv2-miR-H7-3p, hsa-miR-194*, hsa-miR-3152, kshv-miR-K12-4-3p, hsa-miR-665 and hsa-miR-3659 and downregulation of hsa-miR-126*, hsa-miR-484, hsa-miR-330-3p and hsa-miR-3653. qRT-PCR analysis confirmed the microarray findings for hsa-miR-194* and hsa-miR-665 (p < 0.001 each) with AUC values of 0.811 (95% CI 0.694-0.927) and 0.817 (95% CI 0.704-0.930), respectively, in ROC analysis.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [32]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [4]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• 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: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: EC9706-R cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: Het-1A cells; Esophagus; Homo sapiens (Human); CVCL_3702
• 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 Apoptosis Detection assay
• Mechanism Description: Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via down-regulation of PTEN.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [14]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Down-regulation
• 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) [14]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Up-regulation
• 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) [14]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• 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 kinase 1 (SPHK1) [14]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• 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.

Oesophagogastric cancer [ICD-11: 2B71]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [14]

• Resistant Disease: Gastroesophageal cancer [ICD-11: 2B71.0]
• Molecule Alteration: Expression; Down-regulation
• 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 kinase 1 (SPHK1) [14]

• Resistant Disease: Gastroesophageal cancer [ICD-11: 2B71.0]
• Molecule Alteration: Expression; Up-regulation
• 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: hsa-mir-135a [6]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Sp1/DAPK2 signaling signaling pathway; Inhibition; hsa05231
• 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: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MGC-803/OXA cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901/OXA cells; Gastric; Homo sapiens (Human); CVCL_B0A1
• In Vitro Model: SNU-5 cells; Gastric; Homo sapiens (Human); CVCL_0078
• 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: miR135a promotes gastric cancer progression and resistance to oxaliplatin. The mechanism whereby miR135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPk2 pathway signaling.

Key Molecule: BLACAT1 overlapping LEMD1 locus (BLACAT1) [33]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BLACAT1/miR361/ABCB1 signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; 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 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: BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.

Key Molecule: BLACAT1 overlapping LEMD1 locus (BLACAT1) [33]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• 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
• Cell Pathway Regulation: miR125a/hexokinase 2 pathway; Regulation; N.A.
• 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: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.

Key Molecule: hsa-mir-361 [33]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BLACAT1/miR361/ABCB1 signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; 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 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: BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.

Key Molecule: hsa-miR-383 [7]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Down-regulation
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: CircLRCH3 and FGF7 levels were up-regulated, while miR-383-5p level was reduced in OXA-resistant GC tissues and cells. Depletion of circLRCH3 attenuated the resistance of OXA-resistant cells to OXA. CircLRCH3 silence reduced OXA resistance by regulating miR-383-5p. Besides, miR-383-5p elevated OXA sensitivity of GC cells by repressing FGF7. Moreover, the deletion of circLRCH3 increased OXA sensitivity in vivo.

Key Molecule: hsa-miR-433 [7]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC-7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole-genome and miRNA sequencing chips; qRT-PCR; Western blot; ChIP assay; RIP assay; Dual-luciferase reporter assay; RNA pull-down assay
• Experiment for Drug Resistance: CCK8 assay; Apoptosis assay; Transwell assay
• Mechanism Description: Our findings illustrate that NORAD, activated by the oxidative stress, can positively regulate ATG5 and ATG12 and enhance the autophagy flux by sponging miR-433-3p.

Key Molecule: hsa-miR-195 [7]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR-195-5p signalling; Regulation; N.A.
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vivo Model: GC tissues model; Homo sapiens
• Experiment for Molecule Alteration: qRT-PCR; Western blot; Luciferase assay
• Experiment for Drug Resistance: Cell viability assay; EdU incorporation assay; Apoptosis analysis
• Mechanism Description: Taken together, our findings demonstrated that HOTAIR regulates ABCG2 induced resistance of GC to oxaliplatin through miR-195-5p signalling and illustrate the great potential of developing new therapeutic targets for GC patients.

Key Molecule: hsa-miR-421 [9]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATM/Chk2/p53; Regulation; N.A.
• 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: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: SGC-7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: RIP experiments; Dual-luciferase reporter assay; PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Next, Pull-down assay and dual-luciferase reporter assay verified that miR-421 was a target of circ_0001546 while ATM (Ataxia telangiectasia mutated) was target by miR-421

Key Molecule: hsa-miR-200c [7]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Gastric cancer patients; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: qRT-PCR analysis was used to validate the results from the RNA sequencing. The expression levels of the DE miRNAs were analyzed following the chemotherapy cycles. The expression levels of miR-378f, miR-200c-3p, and miR-885-5p were higher in the group receiving chemotherapy for fewer than 4 cycles than in the group receiving chemotherapy for 4-7 cycles. The expression of miR-4666a-3p was not detectable in the qRT-PCR measurement. The expression of miR-378f was significantly downregulated (p = 0.0041) (Figure 2).

Key Molecule: hsa-miR-885 [7]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Gastric cancer patients; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: qRT-PCR analysis was used to validate the results from the RNA sequencing. The expression levels of the DE miRNAs were analyzed following the chemotherapy cycles. The expression levels of miR-378f, miR-200c-3p, and miR-885-5p were higher in the group receiving chemotherapy for fewer than 4 cycles than in the group receiving chemotherapy for 4-7 cycles. The expression of miR-4666a-3p was not detectable in the qRT-PCR measurement. The expression of miR-378f was significantly downregulated (p = 0.0041) (Figure 2).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [33]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• 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
• Cell Pathway Regulation: miR125a/hexokinase 2 pathway; Regulation; N.A.
• 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: 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: BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [33]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• 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
• Cell Pathway Regulation: miR125a/hexokinase 2 pathway; Regulation; N.A.
• 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: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Dihydroorotate dehydrogenase (DHODH) [34]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• 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: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo.

Key Molecule: Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) [34]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• 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: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo.

Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1) [18]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MKN45 cells; Liver; Homo sapiens (Human); CVCL_0434
• In Vitro Model: NUGC3 cells; Gastric; Homo sapiens (Human); CVCL_1612
• Experiment for Molecule Alteration: Expression profiles
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Transforming growth factor beta 1 (TGFB1) [21]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FAO signaling pathway; Activation; hsa04550
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Enzyme-linked immunosorbent assay
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.

Key Molecule: hsa-miR-145-5p [21]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FAO signaling pathway; Activation; hsa04550
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• 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: Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.

Key Molecule: MACC1 antisense RNA 1 (MACC1-AS1) [21]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FAO signaling pathway; Activation; hsa04550
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• 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: Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor E2F1 (E2F1) [6]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Sp1/DAPK2 signaling signaling pathway; Inhibition; hsa05231
• 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: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: MGC-803/OXA cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901/OXA cells; Gastric; Homo sapiens (Human); CVCL_B0A1
• In Vitro Model: SNU-5 cells; Gastric; Homo sapiens (Human); CVCL_0078
• 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: miR135a promotes gastric cancer progression and resistance to oxaliplatin. The mechanism whereby miR135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPk2 pathway signaling.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [14]

• Resistant Disease: Gastric cardia adenocarcinoma [ICD-11: 2B72.2]
• Molecule Alteration: Expression; Down-regulation
• 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: Sphingosine kinase 1 (SPHK1) [14]

• Resistant Disease: Gastric cardia adenocarcinoma [ICD-11: 2B72.2]
• Molecule Alteration: Expression; Up-regulation
• 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 Sensitive Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-216a [8]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MKN45 cells; Liver; Homo sapiens (Human); CVCL_0434
• 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: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Quantitative analyses revealed substantial downregulation of miR-216a-5p in both clinical GC samples and cellular models relative to matched non-neoplastic mucosal tissues and normal epithelial controls. Functional assays demonstrated that miR-216a-5p inhibited GC cell proliferation and migration while enhancing their sensitivity to OXA. Mechanistically, miR-216a-5p directly targeted and downregulated ZBTB2, thereby modulating GC cell growth and chemoresistance. Rescue experiments confirmed that ZBTB2 overexpression partially reversed the effects of miR-216a-5p on GC cells. In vivo studies further supported the tumour-suppressive role of miR-216a-5p and its regulation of ZBTB2.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-195-5p [35]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR 195 5p inhibit multi drug resistance of gastric cancer cells via downregulating ZNF139.

Key Molecule: Protein lin-28 homolog A (CSDD1) [36]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• 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: Lin28/miR107 pathway; Regulation; N.A.
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.

Key Molecule: Protein lin-28 homolog B (CSDD2) [36]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• 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: Lin28/miR107 pathway; Regulation; N.A.
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.

Key Molecule: hsa-miR-107 [36]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• 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: Lin28/miR107 pathway; Regulation; N.A.
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.

Key Molecule: hsa-mir-218 [37]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• 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 Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-218 may inhibit efflux of ADM and oxaliplatin by down-regulating P-gp expression.

Key Molecule: hsa-mir-204 [38]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: GTL-16 cells; Gastric; Homo sapiens (Human); CVCL_7668
• In Vivo Model: CD1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [37]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• 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
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-218 may inhibit efflux of ADM and oxaliplatin by down-regulating P-gp expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger protein with KRAB and SCAN domains 1 (ZKSCAN1) [35]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR 195 5p inhibit multi drug resistance of gastric cancer cells via downregulating ZNF139.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [37]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• 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 Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Key Molecule: Smoothened homolog (SMO) [37]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• 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
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [38]

• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: GTL-16 cells; Gastric; Homo sapiens (Human); CVCL_7668
• In Vivo Model: CD1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil.

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