Disease Information

General Information of the Disease (ID: DIS00092)

• Name: Ovarian cancer
• ICD: ICD-11: 2C73

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  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 Drug

Approved Drug(s) 10 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Adrenomedullin (ADM) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.98E-25; Fold-change: 3.57E-01; Z-score: 1.20E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: RNA seq
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The present study demonstrated that ADM can induce cisplatin chemoresistance in human ovarian epithelial carcinoma cells through reprogramming of glucose metabolism via upregulation of PKM2 and subsequently contribute to cancer prevention and therapy. This conclusion is supported by the following observations: (1)ADMexpression was upregulated in cisplatin-resistant EOC cells; (2) ADM attenuated cisplatin-inhibited cell survival and cisplatin-induced apoptosis in sensitive EOC cells; (3) knockdown of ADM enhanced cisplatin chemosensitivity of cisplatin-resistant EOC cells; (4) ADM enhanced glycolysis in cisplatin-sensitive EOC cells; (5) knockdown of ADM significantly inhibited glycolysis in cisplatin-resistant EOC cells; and (6) ADM significantly upregulated PKM2 protein level, the key enzyme during glycolysis.

Key Molecule: Adrenomedullin (ADM) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.98E-25; Fold-change: 3.57E-01; Z-score: 1.20E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 EOC cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: RNA seq
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The present study demonstrated that ADM can induce cisplatin chemoresistance in human ovarian epithelial carcinoma cells through reprogramming of glucose metabolism via upregulation of PKM2 and subsequently contribute to cancer prevention and therapy. This conclusion is supported by the following observations: (1) ADM expression was upregulated in cisplatin-resistant EOC cells; (2) ADM attenuated cisplatin-inhibited cell survival and cisplatin-induced apoptosis in sensitive EOC cells; (3) knockdown of ADM enhanced cisplatin chemosensitivity of cisplatin-resistant EOC cells; (4) ADM enhanced glycolysis in cisplatin-sensitive EOC cells; (5) knockdown of ADM significantly inhibited glycolysis in cisplatin-resistant EOC cells; and (6) ADM significantly upregulated PKM2 protein level, the key enzyme during glycolysis.

Key Molecule: Acyl-CoA synthetase short-chain family member 2 (ACSS2) [81]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2.

Key Molecule: B-cell lymphoma 6 (Bcl6) [82]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FoxO signaling pathway; Activation; hsa04068
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues.

Key Molecule: BCL2 associated athanogene 5 (BAG5) [82]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FoxO signaling pathway; Activation; hsa04068
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues.

Key Molecule: Tumor necrosis factor receptor-associated protein 1 (TRAP1) [83]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival.

Key Molecule: Tumor necrosis factor receptor-associated protein 1 (TRAP1) [83]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP2 inversely correlates with stage and grade and directly correlates with survival.

Key Molecule: Glutathione biosynthesis bifunctional protein GshAB (GSHAB ) [84]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Thus, this study aimed to elucidate the underlying mechanisms by which ovarian cancer cells acquire CDDP resistance.

Key Molecule: Acyl-CoA synthetase short-chain family member 2 (ACSS2) [81]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: BALB/c nude mice; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK3.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Collagen alpha-1(I) chain (COL1A1) [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.59E-01; Fold-change: 1.41E-03; Z-score: 5.12E-02
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.02E-01; Fold-change: 9.56E-02; Z-score: 1.84E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.48E-03; Fold-change: 8.57E-02; Z-score: 4.05E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: Phosphatase and tensin homolog (PTEN) [15]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.10E-01; Fold-change: 7.35E-03; Z-score: 2.48E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [16]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.65E-01; Fold-change: 6.28E-02; Z-score: 1.53E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vitro Model: OVCA3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: OVCA633 cells; Ovary; Homo sapiens (Human); CVCL_W776
• In Vitro Model: OVCA680 cells; Ovary; Homo sapiens (Human); CVCL_W781
• In Vitro Model: OVCA702 cells; Ovary; Homo sapiens (Human); CVCL_W782
• In Vitro Model: OVCA810 cells; Ovary; Homo sapiens (Human); CVCL_W783
• Experiment for Molecule Alteration: Combined immunostaining and chromosome painting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: One possible down-stream candidate is XIAP, which is the most potent direct inhibitor of caspases and apoptosis among all human IAP family proteins. Down-regulated expression of XIAP has been shown to induce apoptosis in chemoresistant human ovarian cancer cells. Down-regulation of XIST might increase the expression level of XIAP and block drug-induced apoptosis to cause resistance phenotype.

Key Molecule: Glutamate--cysteine ligase catalytic subunit (GCLC) [9]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.60E-01; Fold-change: 5.39E-02; Z-score: 6.08E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Quinone reductase 1 (NQO1) [9]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.99E-05; Fold-change: 3.77E-01; Z-score: 7.06E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [19]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.12E-03; Fold-change: 3.37E-01; Z-score: 3.94E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: OVCAR4 cells; Ovary; Homo sapiens (Human); CVCL_1627
• In Vitro Model: CH1 cells; Abdomen; Homo sapiens (Human); CVCL_D177
• In Vitro Model: 41M cells; Ascites; Homo sapiens (Human); CVCL_4993
• In Vitro Model: PXN94 cells; Pelvis; Homo sapiens (Human); CVCL_4994
• In Vitro Model: HX62 cells; Esophagus; Homo sapiens (Human); CVCL_4995
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: ATP cell viability assay
• Mechanism Description: CCND1 may induce cisplatin resistance both through cell cycle control and inhibition of cellular apoptosis pathways, which have been previously observed37 and supported by our CCND1 knockdown study. The role of CCND1 in cell cycle control is well documented. CCND1 accumulates in cells at middle and late G1 phase and stimulate G1 progression to S phase. The proportion of parental cells in G1/0 correlated with the cisplatin sensitivity, with 833K cells having the highest G1/0 population cells and lowest EC50 value and GCT27 the lowest G1/0 population but highest EC50 score.

Key Molecule: Transcription factor E2F3 (E2F3) [20]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.61E-05; Fold-change: 3.06E-01; Z-score: 8.90E+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 migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR 210 3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

Key Molecule: GSK3B interacting protein (GSKIP) [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.33E-03; Fold-change: 2.52E-01; Z-score: 4.79E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Key Molecule: Protein jagged-1 (JAG1) [26]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.31E-01; Fold-change: 1.93E-02; Z-score: 2.21E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JAG1/Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The forced expression of miR-199b-5p could suppress ovarian cancer cell growth and sensitize the cells to cisplatin-induced cytotoxicity. On the other hand, as a direct target of miR-199b-5p in ovarian cancer cells, JAG1 depletion by siRNAs also resulted in cell growth retardation and sensitization to cisplatin-induced cytotoxicity. In contrast, activating Notch1 signaling by JAG1 or repressing miR-199b-5p by anti-miR-199b-5p could induce the activity of JAG1-Notch1 signaling in ovarian cancer cells. The loss of miR-199b-5p increased the activation of JAG1-Notch1 signaling, which in turn promoted ovarian cancer progression and acquired chemoresistance.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [29]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.16E-01; Fold-change: 1.48E-02; Z-score: 5.20E-01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: Glutamate--cysteine ligase regulatory subunit (GCLM) [9]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.55E-01; Fold-change: 1.35E-01; Z-score: 1.57E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Protein salvador homolog 1 (SAV1) [32]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.74E-01; Fold-change: -1.96E-02; Z-score: -7.48E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: Activin receptor-like kinase 7 (ALK7) [40]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.94E-01; Fold-change: -1.00E-01; Z-score: -1.42E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Nodal/ALK7 signaling pathway; Inhibition; hsa04350
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: We found that miR-376c increased cell proliferation and survival, as well as spheroid formation, in part by targeting ALk7. We have also provided evidence that the Nodal-ALk7 pathway is involved in cisplatin-induced ovarian cancer cell death and that miR-376c might promote chemoresistance.

Key Molecule: Programmed cell death protein 4 (PDCD4) [43], [44]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.37E-01; Fold-change: -1.28E-01; Z-score: -1.28E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: A2780-CP cells; Ovary; Homo sapiens (Human); CVCL_H745
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-21 enhanced the sensitivity of ovarian cancer cells to cisplatin, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, downregulation of PDCD4 results in drug resistance via enhanced expression of c-IAP2 and MDR1. And the enhancement of miR-106a expression contributes to the generation of CDDP-resistant ovarian cancer cells, partly by targeting PDCD4. PDCD4 promoted CDDP-induced apoptosis mainly through the death receptor-mediated pathway.

Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4) [50]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.19E-03; Fold-change: -2.65E-01; Z-score: -3.77E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Matrix protein P1 (HSPD1) [51]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.17E-02; Fold-change: -3.08E-01; Z-score: -2.84E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulations of PkM2 and HSPD1 involved in MDR in ovarian cancer.

Key Molecule: Neuron navigator 3 (NAV3) [52]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.66E-02; Fold-change: -5.04E-01; Z-score: -3.02E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Several miRNAs that are increased in cisplatin-resistant cells. We show that most of these do not directly contribute to cisplatin resistance. Interestingly, miR-21-3p, the passenger strand of the known oncomiR, directed increased resistance to cisplatin in a range of ovarian cell lines. This effect was specific to the star strand, as miR-21-5p had the opposite effect and actually increased sensitivity of A2780 cells to cisplatin. We identify NAV3 as a potential target of miR-21-3p and show that knockdown of NAV3 increases resistance.

Key Molecule: Cullin-5 (CUL5) [61]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Dual luciferase assay; qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [9]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.41E-06; Fold-change: 3.22E-01; Z-score: 4.97E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutathione S-transferase P (GSTP1) [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.41E-03; Fold-change: 1.16E-01; Z-score: 4.28E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [17]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.10E-06; Fold-change: 5.88E-01; Z-score: 1.13E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that EZH2 was overexpressed in cisplatin-resistant ovarian cancer cells compared with cisplatin-sensitive cells. Knockdown of EZH2 by RNA interference (RNAi) resensitized drug-resistant ovarian cancer A2780/DDP cells to cisplatin and decreased the level of H3K27 trimethylation (H3K27me3).

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [25]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.91E-04; Fold-change: 2.12E-01; Z-score: 6.38E+00
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Owing to the aberrant methylation engendered by DNMT1 over-expression, miR-30a-5p, and miR-30c-5p levels dropped significantly in cisplatin-resistant ovarian cancer (OC) cells. On the contrary, miR-30a/c-5p inhibited Snail and DNMT1 directly. Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC.

Key Molecule: Cancer susceptibility 11 (CASC11) [57]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Key Molecule: hsa-mir-27a [61]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Key Molecule: hsa-miR-210-3p [20]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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 invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR 210 3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

Key Molecule: hsa-mir-128a [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: Long non-protein coding RNA 161 (LINC00161) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: hsa-mir-503 [62]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR503 might be a sensitizer to cisplatin treatment in ovarian cancer by targeting PI3k p85 and participating in the regulation of the PI3k/Akt signaling pathway. The role of miR503 in regulating cisplatin sensitivity in ovarian cancer cells is correlated with the activation of PI3k/Akt signaling.

Key Molecule: hsa-mir-21 [63]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN.

Key Molecule: hsa-miR-199a-3p [64]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR199a/DDR1 signaling pathway; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: IOSE386 cells; Ovary; Homo sapiens (Human); CVCL_E230
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Wound healing assay
• Mechanism Description: Suppressing miR199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. Overexpression of miR199a-3p significantly impaired the migratory, invasive, and tumorigenic capabilities of ovarian cancer cells as well as enhanced cisplatin resistance through inhibiting DDR1 expression.

Key Molecule: hsa-miR-30a-5p [65]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: COC1/DDP cells; Ovary; Homo sapiens (Human); CVCL_6892
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miRNA-30a-5p was able to promote cell growth and colony forming ability, and enhance cell migration and invasion.

Key Molecule: hsa-miR-509-3p [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: hsa-mir-137 [66]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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 colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: c-Myc signaling pathway; Activation; hsa05230
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: In resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin.

Key Molecule: hsa-mir-216a [67]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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 colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-216a increases cisplatin resistance in ovarian cancer cells via downregulating PTEN.

Key Molecule: hsa-miR-149-5p [32]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: hsa-miR-770-5p [68]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• Experiment for Molecule Alteration: qRT-PCR; ISH
• Experiment for Drug Resistance: Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting and reducing the level of ERCC2.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [9]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Pvt1 oncogene (PVT1) [50]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: hsa-mir-130a [15]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: hsa-mir-374a [15]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: hsa-miR-21-3p [52]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Several miRNAs that are increased in cisplatin-resistant cells. We show that most of these do not directly contribute to cisplatin resistance. Interestingly, miR-21-3p, the passenger strand of the known oncomiR, directed increased resistance to cisplatin in a range of ovarian cell lines. This effect was specific to the star strand, as miR-21-5p had the opposite effect and actually increased sensitivity of A2780 cells to cisplatin. We identify NAV3 as a potential target of miR-21-3p and show that knockdown of NAV3 increases resistance.

Key Molecule: hsa-mir-128a [28]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: hsa-miR-224-5p [69]

• Resistant Disease: Ovarian papillary serous carcinoma [ICD-11: 2C73.4]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PRKCD signaling pathway; Inhibition; hsa05208
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: PRkCD, known as protein kinase C deta, is a PkC isozyme that acts as a substrate for caspase-3. Its activity is believed to be required for apoptosis induced by DNA damaging agents such as cisplatin, mitomycin C and doxorubicin. miR-224-5p could negatively regulate the expression of PRkCD, and together with PRkCD, they can serve as novel predictors and prognostic biomarkers for OPSC patient response to overall disease-specific survival. The PRkCD pathway may be a molecular mechanism through which miR-224-5p exerts its functions as an oncogene and enhancer of chemoresistance to cisplatin in OPSC patients.

Key Molecule: hsa-mir-21 [70]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk1/c-Jun pathway; Activation; hsa04010
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vitro Model: A2780CP20 cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Alamar blue dye assay
• Mechanism Description: Blocking the JNk-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNk-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.

Key Molecule: hsa-mir-489 [71]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 overexpression results in an inhibition of SkOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SkOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SkOV3, OVCAR3, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression.

Key Molecule: hsa-miR-199b-5p [26]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JAG1/Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The forced expression of miR-199b-5p could suppress ovarian cancer cell growth and sensitize the cells to cisplatin-induced cytotoxicity. On the other hand, as a direct target of miR-199b-5p in ovarian cancer cells, JAG1 depletion by siRNAs also resulted in cell growth retardation and sensitization to cisplatin-induced cytotoxicity. In contrast, activating Notch1 signaling by JAG1 or repressing miR-199b-5p by anti-miR-199b-5p could induce the activity of JAG1-Notch1 signaling in ovarian cancer cells. The loss of miR-199b-5p increased the activation of JAG1-Notch1 signaling, which in turn promoted ovarian cancer progression and acquired chemoresistance.

Key Molecule: hsa-mir-130a [29], [72]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR130a/XIAP signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-130a could suppress XIAP expression and sensitize A2780/DDP cells to cisplatin. And finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: hsa-mir-21 [44]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780-CP cells; Ovary; Homo sapiens (Human); CVCL_H745
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The inhibition of miR-21 enhanced the sensitivity of ovarian cancer cells to cisplatin, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, downregulation of PDCD4 results in drug resistance via enhanced expression of c-IAP2 and MDR1.

Key Molecule: hsa-mir-106a [43]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The enhancement of miR-106a expression contributes to the generation of CDDP-resistant ovarian cancer cells, partly by targeting PDCD4. PDCD4 promoted CDDP-induced apoptosis mainly through the death receptor-mediated pathway.

Key Molecule: hsa-mir-106a [73]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of miR-106a dramatically decreased antiproliferative effects and apoptosis in-duced by cisplatin in A2780 cells, while overexpression of miR-106a significantly increased antiprolif-erative effects and apoptosis induced by cisplatin in A2780/DDP cells. Furthermore, miR-106a inhibited cell survival and cisplatin resistance through downregulating the expression of Mcl-1. Mcl-1 was a di-rect target of miR-106a.

Key Molecule: hsa-mir-29a [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-29b [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-29c [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-146a [74]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Higher expression of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease.

Key Molecule: hsa-mir-150 [74]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Higher expression of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease.

Key Molecule: hsa-mir-141 [75]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780 DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-141 regulates the expression of kEAP1 and that the repression of kEAP1 contributes to cisplatin resistance. Inhibition of NF-kB signaling enhances miR-141-mediated cisplatin sensitivity.

Key Molecule: hsa-mir-130a [76]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/PTEN/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CIS cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-130a, acting as an intermediate, might regulate cisplatin resistance by activating PI3k/Akt/PTEN/mTOR and ABC superfamily drug transporter pathways in ovarian cancer cells.

Key Molecule: hsa-mir-93 [77]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-93, a new family member of PTEN regulator, blocks PTEN translation leading to activation of the AkT pathway and played an important role in regulating cisplatin chemosensitivity pathway in ovarian cancer.

Key Molecule: hsa-mir-125b [78]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bak1 was a direct target of miR-125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. miR-125b has a sig-nificantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression.

Key Molecule: hsa-mir-376c [40]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• 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: Nodal/ALK7 signaling pathway; Inhibition; hsa04350
• Cell Pathway Regulation: Spheroid formation; Activation; hsa04140
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: We found that miR-376c increased cell proliferation and survival, as well as spheroid formation, in part by targeting ALk7. We have also provided evidence that the Nodal-ALk7 pathway is involved in cisplatin-induced ovarian cancer cell death and that miR-376c might promote chemoresistance.

Key Molecule: hsa-mir-214 [79]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-214 induces cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3'-UTR largely abrogates miR-214-induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.

Key Molecule: X inactive specific transcript (XIST) [16]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vitro Model: OVCA3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: OVCA633 cells; Ovary; Homo sapiens (Human); CVCL_W776
• In Vitro Model: OVCA680 cells; Ovary; Homo sapiens (Human); CVCL_W781
• In Vitro Model: OVCA702 cells; Ovary; Homo sapiens (Human); CVCL_W782
• In Vitro Model: OVCA810 cells; Ovary; Homo sapiens (Human); CVCL_W783
• Experiment for Molecule Alteration: qPCR; Microarray assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: One possible down-stream candidate is XIAP, which is the most potent direct inhibitor of caspases and apoptosis among all human IAP family proteins. Down-regulated expression of XIAP has been shown to induce apoptosis in chemoresistant human ovarian cancer cells. Down-regulation of XIST might increase the expression level of XIAP and block drug-induced apoptosis to cause resistance phenotype.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [25]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Owing to the aberrant methylation engendered by DNMT1 over-expression, miR-30a-5p, and miR-30c-5p levels dropped significantly in cisplatin-resistant ovarian cancer (OC) cells. On the contrary, miR-30a/c-5p inhibited Snail and DNMT1 directly. Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC.

Key Molecule: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) [80]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780/DDP cells; Ovarian; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV3/DDP cells; ovarian; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Immunoprecipitation assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay
• Mechanism Description: Our findings demonstrate a significant reduction in O-GlcNAc glycosylation of SRSF2 at Ser101 in cisplatin-resistant cells, suggesting that O-GlcNAc modification may regulate cisplatin resistance through alternative splicing of AUF1 to generate p45 or p37 isoforms mediated by SRSF2. The current study demonstrated that phosphorylation of hnRNPA1 at S95 site was significantly increased in cisplatin-resistant ovarian cancer. In addition, phosphorylation at Ser95 regulated recruitment of hnRNPA1 to AUF1 pre-mRNA to compete with SRSR2. Therefore, the phosphorylation of hnRNPA1 mediated by DNA-PK and O-GlcNAc glycosylation of SRSF2 might potentially regulate the alternative splicing of AUF1 and contribute to cisplatin resistance in ovarian cancer.

Key Molecule: Serine/arginine-rich splicing factor 2 (SRSF2) [80]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: O-GlcNAc glycosylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780/DDP cells; Ovarian; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV3/DDP cells; ovarian; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Immunoprecipitation assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay
• Mechanism Description: Our findings demonstrate a significant reduction in O-GlcNAc glycosylation of SRSF2 at Ser101 in cisplatin-resistant cells, suggesting that O-GlcNAc modification may regulate cisplatin resistance through alternative splicing of AUF1 to generate p45 or p37 isoforms mediated by SRSF2. The current study demonstrated that phosphorylation of hnRNPA1 at S95 site was significantly increased in cisplatin-resistant ovarian cancer. In addition, phosphorylation at Ser95 regulated recruitment of hnRNPA1 to AUF1 pre-mRNA to compete with SRSR2. Therefore, the phosphorylation of hnRNPA1 mediated by DNA-PK and O-GlcNAc glycosylation of SRSF2 might potentially regulate the alternative splicing of AUF1 and contribute to cisplatin resistance in ovarian cancer.

Key Molecule: Cyclin-H (CCNH) [80]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780/DDP cells; Ovarian; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV3/DDP cells; ovarian; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay
• Mechanism Description: p37 isoform was implicated in the cancer stem cell-like features of ovarian cancer, as knockdown of AUF1 decreased some cancer stem cell like features, including colony formation, spheroid formation, in vivo tumorigenesis, as well as CD133 expression, in cisplatin-resistant ovarian cancer cells. Importantly, restoration of the p37 isoform enhanced cancer stem cell-like characteristics in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Consequently, the differential expression of distinct AUF1 isoforms within diverse cellular contexts may underlie its dualistic impact as either a "promoter" or a "suppressor" in cancer. Targeted inhibition of the p37 isoform could potentially offer a viable therapeutic approach for ovarian cancer patients exhibiting elevated AUF1 expression.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Zinc finger protein SNAI1 (SNAI1) [18]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.60E-02; Fold-change: 3.62E-02; Z-score: 2.09E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells.

Key Molecule: hsa-mir-363 [18]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C5 (ABCC5) [28]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.17E-02; Fold-change: 1.79E-01; Z-score: 3.23E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.01E-02; Fold-change: 1.42E-01; Z-score: 3.33E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [15]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.58E-10; Fold-change: -1.42E-01; Z-score: -6.55E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-8 dye assay; Flow cytometry assay
• Mechanism Description: miR-449a was involved in cisplatin resistance and the overexpression of miR449a increased cisplatin sensitivity mainly through inhibiting proliferation and promoting apoptosis and the direct downregulating the expression of NOTCH1.

Key Molecule: Runt-related transcription factor 3 (RUNX3) [22]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.70E-03; Fold-change: 2.27E-01; Z-score: 3.96E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Inhibition of miR-23a expression increases the sensitivity of A2780 cells to cisplatin possibly by inhibiting the negative regulation by miR-23a target genes that causes inhibition of P-gp protein expression.

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [37]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.19E-01; Fold-change: -5.04E-02; Z-score: -1.06E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [38]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.70E-01; Fold-change: -5.15E-02; Z-score: -1.50E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF2BP1/AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity assay
• Mechanism Description: miR708 increases the susceptibility of ovarian cancer cells to cisplatin by targeting IGF2BP1 and inhibiting Akt signaling. miR708 downregulated the expression of IGF2BP1 and suppressed Akt phosphorylation. Silencing of IGF2BP1 markedly blocked the phosphorylation of Akt.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [39]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.42E-03; Fold-change: -9.65E-02; Z-score: -4.31E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT and DAPI assays
• Mechanism Description: miR509-3p could sensitize ovarian cancer cells to cisplatin treatment by targeting multiple anti-apoptosis genes including BCL2 and promoteing apoptosis in cancer cells.

Key Molecule: Forkhead box protein O3 (FOXO3) [46]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.65E-04; Fold-change: -1.39E-01; Z-score: -6.01E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: Endoglin (ENG) [47]

• Sensitive Disease: Endometrioid ovarian cancer [ICD-11: 2C73.5]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.97E-02; Fold-change: -1.48E-01; Z-score: -2.19E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: TOV112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-370 (miR-370) was down-regulated in endometrioid ovarian cancer cells. In IGROV1 and TOV112D endometrioid ovarian cancer cells, miR-370 suppressed cellular viability and colony formation. miR-370 also (+) endometrioid ovarian cancer cell chemosensitivity to cDDP. Endoglin (ENG) was directly and negatively regulated by miR-370.

Key Molecule: Transcription factor Jun (JUN) [48]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.79E-02; Fold-change: -1.54E-01; Z-score: -2.95E+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: c-Jun/BCL-xl signaling pathway; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer.

Key Molecule: Endothelin-1 receptor (EDNRA) [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.79E-06; Fold-change: -5.92E-01; Z-score: -1.16E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; Transwell assay
• Mechanism Description: Overexpression of miR-30a decreases cellular vitality, invasion, plasticity and EMT. ETAR is identified as a direct target of miR-30a, and their expression is inversely correlated in EOC cell lines and human tissue samples. Upregulation of miR-30a re-sensitizes resistant EOC cells to cisplatinum by binding ETAR. Overexpression of miR-30a inhibits tumor growth in cisplatinum-resistant xenografts.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family F2 (ABCF2) [31]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.49E-01; Fold-change: -1.38E-02; Z-score: -4.72E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [42]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.03E-03; Fold-change: -1.16E-01; Z-score: -3.50E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1294 ameliorated cisplatin-resistant OC malignancy via inhibiting IGF1R.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.41E-06; Fold-change: 3.22E-01; Z-score: 4.97E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Metalloproteinase inhibitor 1 (TIMP1) [8]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.62E-21; Fold-change: 5.18E-01; Z-score: 1.09E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: Cellular tumor antigen p53 (TP53) [8]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.96E-01; Fold-change: 3.21E-02; Z-score: 7.12E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Amphiregulin (AREG) [49]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.95E-01; Fold-change: -1.58E-01; Z-score: -8.98E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Bevacizumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: EPH receptor B4 (EPHB4) [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Bevacizumab
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.42E-09; Fold-change: 2.17E-01; Z-score: 6.07E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Primary pulmonary lymphoepithelioma-like carcinoma tissue; N.A.
• In Vivo Model: Athymic BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: EphB4 was overexpressed in BV-resistant xenograft models instead of other common receptor tyrosine kinases. In addition, when coadministrated with EphB4 blocker NVP-BHG712, the antitumor effect of BV was significantly enhanced in the resistant model, further confirmed the role of EphB4 in BV-resistant ovarian cancer. These results indicate that NVP-BHG712 reverses EphB4 overexpression-mediated resistance to BV.

Anagrelide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [4]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Anagrelide
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.31E-10; Fold-change: -2.89E-01; Z-score: -6.73E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Mestranol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [4]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Mestranol
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.31E-10; Fold-change: -2.89E-01; Z-score: -6.73E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.41E-06; Fold-change: 3.22E-01; Z-score: 4.97E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The upregulation of GST-Pi cause excessive intensity of detoxification of cytostatics, affect drug metabolism and influence the effects of chemotherapy, which results in resistance for paclitaxel in the ovarian cancer cells.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Tubulin beta-3 chain (TUBB3) [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.94E-02; Fold-change: 8.18E-02; Z-score: 2.01E+00
• 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: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [23]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-01; Fold-change: 2.25E-02; Z-score: 9.05E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Down-regulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression.

Key Molecule: CUB domain-containing protein 1 (CDCP1) [27]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.85E-05; Fold-change: 1.92E-01; Z-score: 7.30E+00
• 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: MYC/WNT/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: NMRI-nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Time course proliferation assay; Flow cytometry assay
• Mechanism Description: CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AkT pathways.

Key Molecule: Zinc finger protein PLAGL2 (PLAGL2) [27]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.68E-03; Fold-change: 1.41E-01; Z-score: 3.84E+00
• 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: MYC/WNT/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: NMRI-nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Time course proliferation assay; Flow cytometry assay
• Mechanism Description: CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AkT pathways.

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [30]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.74E-04; Fold-change: 1.06E-01; Z-score: 4.97E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TLR/MyD88 signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: In the present study, flow cytometric assays were used to detect the apoptosis of A2780 cells after down-regulation of miRNA-149. We found that down-regulation of miRNA-149 decreased the apoptosis induced by paclitaxel when compared to the control group. Furthermore, we showed that down-regulation of miRNA-149 in A2780 cells (+) the expression of the anti-apoptotic protein Bcl-2 and inhibited the expression of the pro-apoptotic protein bax, which may have led to paclitaxel resistance.

Key Molecule: Growth protein 5 inhibitor (ING5) [34]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.54E-01; Fold-change: -2.41E-02; Z-score: -9.83E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/Taxol cells; Ovary; Homo sapiens (Human); CVCL_IJ13
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Apoptosis analysis by FITC immunofluorescence
• Mechanism Description: miR1307 promotes ovarian cancer cell chemoresistance by targeting the ING5 expression.

Key Molecule: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) [35]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.45E-01; Fold-change: -2.62E-02; Z-score: -1.00E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) is a protein that binds to HIF-1alpha and inhibits its transcriptional activity. HIF1AN is a potential miR-135a target listed in both the TargetScan and PicTar databases. miR-135a-mediated paclitaxel resistance is in part mediated by downregulation of APC.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurogenic locus notch homolog protein 3 (NOTCH3) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.90E-11; Fold-change: -2.73E-01; Z-score: -7.13E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST assay; Spheroid formation assay; Colony-forming assay; TUNEL assay; Wound healing assay
• Mechanism Description: microRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.

Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [24]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.27E-01; Fold-change: 2.19E-02; Z-score: 8.36E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Wound healing assay; Invasion assay; CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-630 inhibitor attenuated chemoresistant epithelial ovarian cancer proliferation and invasion, probably by targeting APAF-1, re-sensitizing the cells to chemotherapy.

Key Molecule: Superoxide dismutase Mn (SODM) [41]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.62E-01; Fold-change: -1.14E-01; Z-score: -1.54E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR146a/SOD2/ROS signaling pathway; Regulation; N.A.
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL Assay
• Mechanism Description: miR146a downregulates the expression of SOD2 and enhances ROS generation, leading to increased apoptosis, inhibition of proliferation, and enhanced sensitivity to chemotherapy.

Carboplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Metalloproteinase inhibitor 1 (TIMP1) [8]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.62E-21; Fold-change: 5.18E-01; Z-score: 1.09E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: hsa-miR-34c-5p [49]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Key Molecule: hsa-miR-634 [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Cellular tumor antigen p53 (TP53) [8]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: Pvt1 oncogene (PVT1) [8]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Amphiregulin (AREG) [49]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Ribosomal protein S6 kinase alpha-3 (RPS6KA3) [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin-8 (IL8) [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.91E-02; Fold-change: 2.94E-01; Z-score: 1.93E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Cysteine-rich motor neuron 1 protein (CRIM1) [45]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.22E-05; Fold-change: -1.29E-01; Z-score: -7.42E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of five platinum-associated genes (CRIM1, IFIT2, OAS1, kCNMA1 and GRAMD1B). over-expression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin.

Key Molecule: Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) [45]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of five platinum-associated genes (CRIM1, IFIT2, OAS1, kCNMA1 and GRAMD1B). over-expression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin.

Key Molecule: Carboxylesterase 4A (CES4A) [59]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Missense mutation; p.P55S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1) [59]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Missense mutation; p.M889K
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Interleukin 6 receptor (IL6R) [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Interleukin-8 (IL8) [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Interleukin 6 receptor (IL6R) [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Fibroblast growth factor 2 (FGF1) [54]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780DPP cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Caov-3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: qRT-PCR; Immunoblotting assay
• Experiment for Drug Resistance: MTT assay; In vitro chemosensitivity assay
• Mechanism Description: Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7027 re-sensitised resistant cells.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 11 (CASC11) [57]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Key Molecule: hsa-miR-193b-3p [45]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of five platinum-associated genes (CRIM1, IFIT2, OAS1, kCNMA1 and GRAMD1B). over-expression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) [58]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: Functional experiments using both transgenic mouse models and human cancer-derived models confirmed the critical tumor-suppressive role of OTUB2 in ovarian cancer. Intriguingly, we identified sorting nexin 29 pseudogene 2 (SNX29P2), an ill-defined protein with biased expression in ovarian tissue, as a bona fide substrate of OTUB2. The deubiquitination and stabilization of SNX29P2 by OTUB2 promotes the interaction between the E3 ligase VHL and HIF-1alpha and results in HIF-1alpha degradation, consequently inhibiting the expression of CA9. Activation of CA9 restores OTUB2-mediated inhibition of glycolysis and tumor growth; thus, CA9 inhibitors might be a promising strategy for ovarian cancer treatment.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-141 [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• 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
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Key Molecule: hsa-mir-200c [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• 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
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Key Molecule: Tubulin beta-3 chain (TUBB3) [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• 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: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Tamoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Protein LYRIC (MTDH) [11]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.25E-03; Fold-change: 9.64E-02; Z-score: 3.90E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell titer glo assay
• Mechanism Description: Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [36]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.96E-01; Fold-change: -3.18E-02; Z-score: -1.12E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: CYP450-Glo TM CYP 3A4 assay, RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [36]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.66E-02; Fold-change: -6.09E-02; Z-score: -1.88E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [36]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.76E-03; Fold-change: -2.41E-01; Z-score: -4.53E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [36]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.53E-04; Fold-change: -2.43E-01; Z-score: -6.49E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Butorphanol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transmembrane protein (TMEFF1) [56]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Butorphanol
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vitro Model: Primary pulmonary lymphoepithelioma-like carcinoma tissue; N.A.
• In Vitro Model: HCK1T cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony Formation assay; Transwell assay; Flow Cytometry
• Mechanism Description: An important issue with compounds for treating ovarian cancer is the development of drug resistance and side effects. Butorphanol is a synthetic opioid. Opioids have been shown to promote or prevent tumor growth and metastasis. Butorphanol Inhibits the Malignant Biological Behaviors of Ovarian Cancer Cells via Down-Regulating the Expression of TMEFF1.

Investigative Drug(s) 1 drug(s) in total

2-hydroxy-5-fluoropyrimidine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [4]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: 2-hydroxy-5-fluoropyrimidine
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.31E-10; Fold-change: -2.89E-01; Z-score: -6.73E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Clinical Trial Drug(s) 1 drug(s) in total

Camptothecin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [33]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Camptothecin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.89E-01; Fold-change: -2.04E-02; Z-score: -7.24E-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: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

References

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