Disease Information

General Information of the Disease (ID: DIS00075)

• Name: Liver cancer
• ICD: ICD-11: 2C12

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

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 32 drug(s) in total

Acetaminophen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (HNF4A-AS1) [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: .; Expression
• Resistant Drug: Acetaminophen
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepaRG cells; Liver; Homo sapiens (Human); CVCL_9720
• Experiment for Molecule Alteration: Knockdown assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Altogether, our study suggests that HNF1alpha-AS1 and HNF4alpha-AS1 affected AILI mainly through alterations of P450-mediated APAP biotransformation in HepaRG cells, indicating an important role of the LncRNAs in AILI.

Key Molecule: HNF1A antisense RNA 1 (HNF1A-AS1) [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: .; Expression
• Resistant Drug: Acetaminophen
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepaRG cells; Liver; Homo sapiens (Human); CVCL_9720
• Experiment for Molecule Alteration: Knockdown assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Altogether, our study suggests that HNF1alpha-AS1 and HNF4alpha-AS1 affected AILI mainly through alterations of P450-mediated APAP biotransformation in HepaRG cells, indicating an important role of the LncRNAs in AILI.

Adenosine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Maternally expressed 3 (MEG3) [2]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: Adenosine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Overexpression assay; Knockdown assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA MEG3 contributes to adenosine-induced cytotoxicity in hepatoma HepG2 cells by downregulated ILF3 and autophagy inhibition via regulation PI3K-AKT-mTOR and beclin-1 signaling pathway.

Arsenic trioxide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-539 [3]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Arsenic trioxide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma.

Baicalein

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: NF-kappaB interacting LncRNA (NKILA) [4]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Baicalein
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: QSG-7701 cells; Liver; Homo sapiens (Human); CVCL_6944
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Luminescent cell viability assay; TUNEL assay; Transwell assay
• Mechanism Description: NkILA inhibited IkBalpha phosphorylation and enhanced the inhibitory roles of baicalein on NF-kB signaling in HCC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NF-kappa-B inhibitor alpha (NFKBIA) [4]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Phosphorylation; Down-regulation
• Sensitive Drug: Baicalein
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: QSG-7701 cells; Liver; Homo sapiens (Human); CVCL_6944
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Luminescent cell viability assay; TUNEL assay; Transwell assay
• Mechanism Description: NkILA inhibited IkBalpha phosphorylation and enhanced the inhibitory roles of baicalein on NF-kB signaling in HCC cells.

Bortezomib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-101 [5]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome maturation protein (POMP) [5]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Carboplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-146a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Cetuximab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

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

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by negatively regulating STAT3 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [7]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by negatively regulating STAT3 expression.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [8], [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: hsa-mir-33a [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Colorectal neoplasia differentially expressed (CRNDE) [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: hsa-miR-613 [11]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: SOX9 signaling pathway; Activation; hsa04024
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.

Key Molecule: Long non-protein coding RNA (RP11-134G8.8) [12]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, the LncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

Key Molecule: Novel transcript, overlapping ACER2 (RP11-363E7.4) [12]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, the LncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

Key Molecule: ENSG00000267194 (RP1-193H18.2 ) [12]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway, the LncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [13]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cytotoxicity; Inhibition; hsa04650
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: xCELLigence assay
• Mechanism Description: HULC promotes the phosphorylation of YB-1 through the extracellular signal-regulated kinase pathway, in turn leads to the release of YB-1 from its bound mRNA.

Key Molecule: Long non-protein coding RNA (NRAL) [14]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NRAL/miR340-5p/Nrf2 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: There is mutual inhibition between NRAL and mir-340-5p and NRAL directly interacts with miR-340-5p to up-regulate the expression of its target, Nrf2, to mediate cisplatin-resistant HCC phenotypes.

Key Molecule: hsa-miR-340-5p [14]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NRAL/miR340-5p/Nrf2 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: There is mutual inhibition between NRAL and mir-340-5p and NRAL directly interacts with miR-340-5p to up-regulate the expression of its target, Nrf2, to mediate cisplatin-resistant HCC phenotypes.

Key Molecule: hsa-mir-363 [15]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR363/Mcl-1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy decreased miR-363 expression in HCC patients. miR-363 expression was also lower in HepG2-R cells than in HepG2 cells, which indicated that the downregulation of miR-363 may be related to cisplatin resistance. overexpression of miR-363 by its mimics can effectively increase the sensitivity of cisplatin-resistant HepG2 cells to cisplatin-induced apoptosis. overexpression of miR-363 could inhibit the expression of Mcl-1 in HepG2-R cells, which implied the inverse correlation between the expression of miR-363 and Mcl-1. More importantly, enforced exogenous Mcl-1 significantly attenuated apoptosis induced by cisplatin. All these results support that Mcl-1 is the target of miR-363 which can enhance sensitivity of human cisplatin-resistant HCC cell cisplatin at least partially.

Key Molecule: hsa-mir-182 [16]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR182/TP53INP1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-182 levels are significantly increased in HCC patients treated with cisplatin-based chemotherapy. Upregulated miR-182 inhibits TP53INP1 expression, which results in sequent cisplatin resistance.

Key Molecule: hsa-mir-146a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-130a [17]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell adhesion; Inhibition; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Oncogenic activation of the Wnt/beta-catenin signaling pathway is common in HCC. Upregulated miR-130a inhibited RUNX3 expression, which resulted in activation of Wnt/beta-catenin signaling and sequent cisplatin resistance.

Key Molecule: hsa-miR-199a-5p [18]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-199a-5p levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. Downregulated miR-199a-5p enhanced autophagy activation by targeting ATG7. Cisplatin-induced downregulation of miR-199a-5p increases cell proliferation by activating autophagy.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis; RNAi assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of HOTAIR expression downregulated the MRP1 expression levels in the k562-imatinib cells and resulted in higher sensitivity to the imatinib treatment. In addition, the activation of PI3k/Akt was greatly attenuated when HOTAIR was knocked down in k562-imatinib cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [8], [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Activation; hsa04110
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Luciferase activity assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Transcription factor SOX-9 (SOX9) [11]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: SOX9 signaling pathway; Activation; hsa04024
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.

Key Molecule: Y-box-binding protein 1 (YBX1) [13]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: xCELLigence assay
• Mechanism Description: HULC promotes the phosphorylation of YB-1 through the extracellular signal-regulated kinase pathway, in turn leads to the release of YB-1 from its bound mRNA.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [15]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR363/Mcl-1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy decreased miR-363 expression in HCC patients. miR-363 expression was also lower in HepG2-R cells than in HepG2 cells, which indicated that the downregulation of miR-363 may be related to cisplatin resistance. overexpression of miR-363 by its mimics can effectively increase the sensitivity of cisplatin-resistant HepG2 cells to cisplatin-induced apoptosis. overexpression of miR-363 could inhibit the expression of Mcl-1 in HepG2-R cells, which implied the inverse correlation between the expression of miR-363 and Mcl-1. More importantly, enforced exogenous Mcl-1 significantly attenuated apoptosis induced by cisplatin. All these results support that Mcl-1 is the target of miR-363 which can enhance sensitivity of human cisplatin-resistant HCC cell cisplatin at least partially.

Key Molecule: Tumor protein p53-inducible nuclear protein 1 (TP53INP1) [16]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR182/TP53INP1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-182 levels are significantly increased in HCC patients treated with cisplatin-based chemotherapy. Upregulated miR-182 inhibits TP53INP1 expression, which results in sequent cisplatin resistance.

Key Molecule: Runt-related transcription factor 3 (RUNX3) [17]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Oncogenic activation of the Wnt/beta-catenin signaling pathway is common in HCC. Upregulated miR-130a inhibited RUNX3 expression, which resulted in activation of Wnt/beta-catenin signaling and sequent cisplatin resistance.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [18]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-199a-5p levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. Downregulated miR-199a-5p enhanced autophagy activation by targeting ATG7. Cisplatin-induced downregulation of miR-199a-5p increases cell proliferation by activating autophagy.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: TPTE pseudogene 1 (TPTEP1) [19]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IL6/STAT3 signaling signaling pathway; Inhibition; hsa04659
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: LncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [9]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3/ABCB1 signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: hsa-mir-503 [20]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 may enhance the sensitivity of BEL-7402 cells to cisplatin and inhibit the cell proliferation by targeting bcl-2. miR503 could interact with bcl-2 and inhibit its expression.

Key Molecule: hsa-miR-199a-3p [21]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. miR199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma.

Key Molecule: hsa-miR-33a-5p [22]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HSPA8 was the direct downstream target gene for miR33a-mediated drug resistance. Inhibition of miR33a-5p expression reduced cisplatin sensitivity in Hep3B and 97L and increased their drug resistance.

Key Molecule: hsa-mir-133a [23]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-miR-326 [23]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-mir-27b [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: hsa-mir-340 [25]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Nrf2 signaling pathway; Activation; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bioinformatics analysis and luciferase assays ofNrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR-340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitorsreactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively,the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistancein hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

Key Molecule: Beclin-1 (BECN1) [26]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepS cells; Liver; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: hsa-mir-30a [26]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: hsa-mir-30a [26]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepS cells; Liver; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [21]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. miR199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [9]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3/ABCB1 signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3k/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR34a.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [20]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase activity assay; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 may enhance the sensitivity of BEL-7402 cells to cisplatin and inhibit the cell proliferation by targeting bcl-2. miR503 could interact with bcl-2 and inhibit its expression.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [21]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. miR199a-3p could increase the cisplatin sensitivity of cholangiocarcinoma cell lines by regulating mTOR expression.

Key Molecule: Heat shock cognate 71 kDa protein (HSPA8) [22]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HSPA8 was the direct downstream target gene for miR33a-mediated drug resistance. Inhibition of miR33a-5p expression reduced cisplatin sensitivity in Hep3B and 97L and increased their drug resistance.

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [23]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: Cyclin-G1 (CCNG1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: NFE2-related factor 2 (NRF2) [25]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Nrf2 signaling pathway; Activation; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bioinformatics analysis and luciferase assays ofNrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR-340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitorsreactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively,the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistancein hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

Key Molecule: Beclin-1 (BECN1) [26]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-30a can sensitize tumor cells to cis-DDP via reducing beclin 1-mediated autophagy.

Key Molecule: NFE2-related factor 2 (NRF2) [27]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KkU-100 cells; Gallbladder; Homo sapiens (Human); CVCL_3996
• In Vitro Model: KkU-M156 cells; Gallbladder; Homo sapiens (Human); CVCL_M260
• In Vitro Model: KkU-M213 cells; Gallbladder; Homo sapiens (Human); CVCL_M261
• In Vitro Model: KkU-M214 cells; Gallbladder; Homo sapiens (Human); CVCL_M264
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Acri-dine orange and ethidium bromide (AO/EB) fluorescent dyes assay
• Mechanism Description: Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant, cytoprotective, and metabolic enzymes, plays important roles in drug resistance and proliferation in cancer cells. Nrf2 mRNA expression of kkU-M156 and kkU-100 cells, representatives of low and high-Nrf2-expressing CCA cells, were silenced using siRNA. After knockdown of Nrf2, the sensitivity of those cells to the cytotoxicity of cisplatin (Cis) was enhanced in association with the increased release of AIF and downregulation of Bcl-xl in both cells.

Dabrafenib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-33a [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Colorectal neoplasia differentially expressed (CRNDE) [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: hsa-miR-589-5p [29]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: 97H cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometric analysis; Spheroid formation assay
• Mechanism Description: miR589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling.

Key Molecule: Ribosomal protein L13a pseudogene 20 (RPL13AP20) [30]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: GSKIP/GSK-3beta signaling pathway; Activation; hsa04550
• Cell Pathway Regulation: Tumorigenesis; Activation; hsa05206
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Microarray assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: HANR bind to GSkIP for regulating the phosphorylation of GSk3beta in HCC, knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin. GSkIP is the direct target of HANR to influence GSk3beta phosphorylation, HANR is physically associated with GSkIP to regulate the GSkIP/GSk3beta pathway.

Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [31]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: TUNEL assays
• Mechanism Description: lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression, and activates PI3k/Akt pathway. Upregulated lncARSR promotes doxorubicin resistance in HCC via modulating PTEN-PI3k/Akt pathway.

Key Molecule: hsa-mir-146a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181 [32]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• 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: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TIMP3 is a tumor suppressor and a validated miR-181 target. Ectopic expression and depletion of miR-181b showed that miR-181b enhanced MMP2 and MMP9 activity and promoted growth, clonogenic survival, migration and invasion of HCC cells that could be reversed by modulating TIMP3 level.

Key Molecule: hsa-let-7a [33]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Caspase-3 is the key executioner caspase in apoptosis. Ectopic expression of let-7adecreased the luciferase activity of a reporter constructcontaining the 30untranslated region of caspase-3. Enforced let-7aexpression increased the resistance in A431 cells andHepG2 cells to apoptosis induced by therapeutic drugs suchas interferon-gamma, doxorubicin and paclitaxel.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [34]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Antisense H19 oligonucleotides transfection induced a marked increase in the percentage of MDR1 promoter methylation and decrease in MDR1 expression in R-HepG2 cells. Thus, the H19 gene is believed to induce P-glycoprotein expression and MDR1-associated drug resistance at least in liver cancer cells through regulation of MDR1 promoter methylation.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [35]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [34]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Antisense H19 oligonucleotides transfection induced a marked increase in the percentage of MDR1 promoter methylation and decrease in MDR1 expression in R-HepG2 cells. Thus, the H19 gene is believed to induce P-glycoprotein expression and MDR1-associated drug resistance at least in liver cancer cells through regulation of MDR1 promoter methylation.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Very low density lipoprotein receptor (VLDLR) [35]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: High mobility group protein HMGI-C (HMGA2) [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Luciferase activity assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Protein-tyrosine phosphatase 1B (PTPN1) [29]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: 97H cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Flow cytometric analysis; Spheroid formation assay
• Mechanism Description: miR589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling.

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [29]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: 97H cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Flow cytometric analysis; Spheroid formation assay
• Mechanism Description: miR589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling.

Key Molecule: Suppressor of cytokine signaling 2 (SOCS2) [29]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: 97H cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Flow cytometric analysis; Spheroid formation assay
• Mechanism Description: miR589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling.

Key Molecule: Suppressor of cytokine signaling 5 (SOCS5) [29]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: 97H cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Flow cytometric analysis; Spheroid formation assay
• Mechanism Description: miR589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [30]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Phosphorylation; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: GSKIP/GSK-3beta signaling pathway; Activation; hsa04550
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical staining
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: HANR bind to GSkIP for regulating the phosphorylation of GSk3beta in HCC, knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin. GSkIP is the direct target of HANR to influence GSk3beta phosphorylation, HANR is physically associated with GSkIP to regulate the GSkIP/GSk3beta pathway.

Key Molecule: Phosphatase and tensin homolog (PTEN) [31]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assays
• Mechanism Description: lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression, and activates PI3k/Akt pathway. Upregulated lncARSR promotes doxorubicin resistance in HCC via modulating PTEN-PI3k/Akt pathway.

Key Molecule: Metalloproteinase inhibitor 3 (TIMP3) [32]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• 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: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TIMP3 is a tumor suppressor and a validated miR-181 target. Ectopic expression and depletion of miR-181b showed that miR-181b enhanced MMP2 and MMP9 activity and promoted growth, clonogenic survival, migration and invasion of HCC cells that could be reversed by modulating TIMP3 level.

Key Molecule: Caspase-3 (CASP3) [33]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Caspase-3 is the key executioner caspase in apoptosis. Ectopic expression of let-7adecreased the luciferase activity of a reporter constructcontaining the 30untranslated region of caspase-3. Enforced let-7aexpression increased the resistance in A431 cells andHepG2 cells to apoptosis induced by therapeutic drugs suchas interferon-gamma, doxorubicin and paclitaxel.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

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

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• 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.

Key Molecule: Glutathione S-transferase (GST) [36]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: GST colorimetric 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.

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [37]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: CYP450-Glo CYP 3A4 assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In this study, resveratrol was a significant inhibitor of CYP3A4 enzyme activity with IC50 value 9.32 ( M). Moreover, the CYP3A4 mRNA levels were reduced after treatment with resveratrol 0.03-fold of the control levels with high significance (p < 0.001).

Key Molecule: Glutathione S-transferase (GST) [37]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Glutathione-S-transferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The Glutathione-S-transferases (GSTs) are a multigene family of dimeric proteins which play a central role in the detoxification of electrophilic xenobiotics and catalyze their conjugation with GSH to electrophilic metabolites, thus rendering them more water soluble. GSTs protect cells from cytotoxic and carcinogenic chemicals. GST activity was decreased by resveratrol in a dose dependent manner. IC50 value was 30.73 M. This results were confirmed by RT-PCR data, where the tested samples changed the GST mRNA level by 0.79-fold (p < 0.01) of control level.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-122 [38]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow Cytometric Analysis
• Mechanism Description: Transfection of miR122 mimics into cultured HepG2 cells induces cell-cycle arrest and sensitizes these cells to doxorubicin by modulating the expression of multidrug resistance genes, ABCB1 and ABCF2.

Key Molecule: hsa-mir-26a [39]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR26a/b can promote apoptosis and sensitize HCC to chemotherapy via suppressing the expression of autophagy initiator ULk.

Key Molecule: hsa-mir-26b [39]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR26a/b can promote apoptosis and sensitize HCC to chemotherapy via suppressing the expression of autophagy initiator ULk.

Key Molecule: hsa-mir-379 [40]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: hsa-mir-383 [41]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vivo Model: BALB/c nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-383 inhibited Dox resistance in HCC cells by downregulating EIF5A2.

Key Molecule: Long non-protein coding RNA 607 (LINC00607) [42]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Real-time RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Key Molecule: hsa-miR-590-5p [43]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: NU/NU nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-590-5p suppresses hepatocellular carcinoma chemoresistance by downregulating YAP1 expression.

Key Molecule: hsa-miR-760 [44]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch1/HES1-PTEN/AKT signaling pathway; Regulation; hsa04330
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Caspase-3 Activity kit assay
• Mechanism Description: miR-760 inhibits Dox-resistance in HCC cells through inhibiting Notch1 and promoting PTEN expression.

Key Molecule: hsa-mir-122 [45]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: miR122/PKM2 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-122 in Huh7/R cells reversed the doxorubicin-resistance through the inhibition of PkM2, inducing the apoptosis in doxorubicin-resistant cancer cells.

Key Molecule: hsa-mir-101 [46]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-101 was downregulated in HCC cell lines, while its overexpression (+) the sensitivity of HepG2 cells to the chemotherapeutic agent DOX by facilitating apoptosis. Of note, Mcl-1 was confirmed as a functional target of miR-101 in HCC, demonstrating that miR-101 may enhance the sensitivity of cancer cells by downregulating Mcl-1 expression.

Key Molecule: WT1 antisense RNA (WT1-AS) [47]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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: JAKT2/STAT3/MAPK signaling pathway; Inhibition; hsa04659
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: EDU assay; Flow cytometry assay
• Mechanism Description: WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1.WT1-AS expression correlated negatively with WT1 expression in HCC tumor tissue. kaplan-Meier curve analysis revealed that WT1-AS expression is a reliable indicator of HCC prognosis. The downregulation of WT1 expression by WT1-AS promoted cell apoptosis by suppressing the JAk/STAT3 signaling pathway. Bioinformatics analysis showed that WT1-AS downregulates WT1 by binding to the TATA region of the WT1 promotor. WT1-AS was also able to reverse WT1-mediated resistance to Dox based chemotherapy in HCC cells.

Key Molecule: WT1 antisense RNA (WT1-AS) [47]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: JAKT2/STAT3/MAPK signaling pathway; Inhibition; hsa04659
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: EDU assay; Flow cytometry assay
• Mechanism Description: WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1.WT1-AS expression correlated negatively with WT1 expression in HCC tumor tissue. kaplan-Meier curve analysis revealed that WT1-AS expression is a reliable indicator of HCC prognosis. The downregulation of WT1 expression by WT1-AS promoted cell apoptosis by suppressing the JAk/STAT3 signaling pathway. Bioinformatics analysis showed that WT1-AS downregulates WT1 by binding to the TATA region of the WT1 promotor. WT1-AS was also able to reverse WT1-mediated resistance to Dox based chemotherapy in HCC cells.

Key Molecule: hsa-mir-27b [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: hsa-mir-503 [48]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: The expression of a number drug resistance related proteins, including multidrug resistance 1, multi drug resistance associated protein 1, DNA excision repair protein ERCC 1, survivin and B cell lymphoma 2, was significantly downregulated by miR 503 overexpression.

Key Molecule: hsa-mir-26b [49]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-26b suppresses NF-kB signaling and thereby sensitized HCC cells to the doxorubicin-induced apoptosis by inhibiting the expression of TAk1 and TAB3.

Key Molecule: hsa-mir-221 [50]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-221 can activate the p53/mdm2 axis by inhibiting MDM2 and, in turn, p53 activation contributes to miR-221 enhanced expression. Moreover, by modulating the p53 axis, miR-221 impacts cell-cycle progression and apoptotic response to doxorubicin in hepatocellular carcinoma-derived cell lines.

Key Molecule: hsa-mir-101 [51]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-101-mediated EZH2 silencing sensitized hepatoblastoma cells to 5-FU- and doxorubicin-induced apoptosis, whereas antagomiR-mediated downregulation of endogenous miR-101 reversed the pro-apoptotic effect.

Key Molecule: Long non-protein coding RNA (BX537613) [52]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA-BX537613 knockdown could sensitize MCF-7/ADR cell to adriamycin again.

Key Molecule: hsa-mir-137 [53]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Immunodeficient NCr nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell titer glo assay assay
• Mechanism Description: Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells.

Key Molecule: hsa-mir-223 [54]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HCC3 cells; Liver; Homo sapiens (Human); CVCL_0C57
• In Vitro Model: LM-6 cells; Liver; Homo sapiens (Human); CVCL_7680
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-223 targeted ABCB1 3'UTR directly, and miR-223 down-regulated ABCB1 at both mRNA and protein levels. The over-expression of miR-223 increased the HCC cellsensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencingof ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition.

Key Molecule: hsa-mir-122 [55]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-122 could modulate the sensitivity of the HCC cells to chemotherapeutic drugs through downregulating MDR related genes MDR-1, GST-Pi, and MRP, antiapoptotic gene Bcl-w and cell cycle related gene cyclin B1.

Key Molecule: hsa-miR-199a-3p [56]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: There is an inverse correlation between the expression of miR-199a-3p and CD44 protein. Transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin. Inhibition of CD44 in CD44+ HCC cell lines using antisense oligonucleotides increased apoptosis, enhanced chemosensitivity, reduced tumorigensis and invasion.

Key Molecule: hsa-miR-199a-3p [57]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Cell invasion assay
• Mechanism Description: The mTOR pathway is activated by multiple extracellular signals, such as growth factors, nutrients, amino acids, hormones, and mitogens leading to the phosphorylation of the translational regulator, phospho-p70S6 kinase, which, in turn, regulates cell proliferation, regulates protein synthesis, and allows progression from the G1 to the S phase of the cell cycle. There is an inverse correlation linking miR-199a-3p and mTOR. miR-199a-3p restoration blocks the G1-S transition of the cell cycle, impairs invasion capability, and sensitizes HCC cells to doxorubicin challenge.

Key Molecule: hsa-mir-122 [58]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V/propidium iodide detection kit
• Mechanism Description: miR-122 enforced expression, as well as cyclin G1 silencing, leads to increased p53 protein stability and transcriptional activity and reduced invasion capability of HCC-derived cell lines, miR-122, through down-regulation of cyclin G1, can trigger apoptosis and increase sensitivity of HCC-derived cells to doxorubicin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [38]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow Cytometric Analysis
• Mechanism Description: Transfection of miR122 mimics into cultured HepG2 cells induces cell-cycle arrest and sensitizes these cells to doxorubicin by modulating the expression of multidrug resistance genes, ABCB1 and ABCF2.

Key Molecule: ATP-binding cassette sub-family F2 (ABCF2) [38]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow Cytometric Analysis
• Mechanism Description: Transfection of miR122 mimics into cultured HepG2 cells induces cell-cycle arrest and sensitizes these cells to doxorubicin by modulating the expression of multidrug resistance genes, ABCB1 and ABCF2.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [48]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: The expression of a number drug resistance related proteins, including multidrug resistance 1, multi drug resistance associated protein 1, DNA excision repair protein ERCC 1, survivin and B cell lymphoma 2, was significantly downregulated by miR 503 overexpression.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [54]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HCC3 cells; Liver; Homo sapiens (Human); CVCL_0C57
• In Vitro Model: LM-6 cells; Liver; Homo sapiens (Human); CVCL_7680
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-223 targeted ABCB1 3'UTR directly, and miR-223 down-regulated ABCB1 at both mRNA and protein levels. The over-expression of miR-223 increased the HCC cellsensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencingof ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High glucose upregulated the level of MDR-1, which can be expected the intracellular accumulation of anticancer drugs. Interestingly, reduced accumulation of doxorubicin was recorded in cells cultured in high glucose media. Curcumin-mediated inhibition of MDR-1 expression can be suggested as critical event leading to retention of anticancer drug in cellular interior.

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

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• 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: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• 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 B5 (ABCB5) [36]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• 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 B5 (ABCB5) [37]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Efflux of rhodamine123 assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Resveratrol can restore the sensitivity of Caco-2 and CEM/ADR5000 cell lines to doxorubicin, through enhancing significantly doxorubicin cytotoxicity. ABC-transporter inhibitors, classified according to their action on ABC-transporters proteins into: 1. Function inhibitors, 2. Expression inhibitors, and 3. Functional and expression inhibitors, which have an ideal characters of ABC-transporters inhibitors. Our results indicate that resveratrol falls into the class 3 inhibitors.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase ULK1 (ULK1) [39]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR26a/b can promote apoptosis and sensitize HCC to chemotherapy via suppressing the expression of autophagy initiator ULk.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [40]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [41]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• In Vivo Model: BALB/c nude mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-383 inhibited Dox resistance in HCC cells by downregulating EIF5A2.

Key Molecule: Cellular tumor antigen p53 (TP53) [42]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [43]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: NU/NU nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-590-5p suppresses hepatocellular carcinoma chemoresistance by downregulating YAP1 expression.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [44]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch1/HES1-PTEN/AKT signaling pathway; Regulation; hsa04330
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Caspase-3 Activity kit assay
• Mechanism Description: miR-760 inhibits Dox-resistance in HCC cells through inhibiting Notch1 and promoting PTEN expression.

Key Molecule: Pyruvate kinase M2 (PKM) [45]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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: miR122/PKM2 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-122 in Huh7/R cells reversed the doxorubicin-resistance through the inhibition of PkM2, inducing the apoptosis in doxorubicin-resistant cancer cells.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [46]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-101 was downregulated in HCC cell lines, while its overexpression (+) the sensitivity of HepG2 cells to the chemotherapeutic agent DOX by facilitating apoptosis. Of note, Mcl-1 was confirmed as a functional target of miR-101 in HCC, demonstrating that miR-101 may enhance the sensitivity of cancer cells by downregulating Mcl-1 expression.

Key Molecule: Cyclin-G1 (CCNG1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: TAK1-binding protein 3 (TAB3) [49]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-26b suppresses NF-kB signaling and thereby sensitized HCC cells to the doxorubicin-induced apoptosis by inhibiting the expression of TAk1 and TAB3.

Key Molecule: Nuclear receptor subfamily 2 group C2 (NR2C2) [49]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-26b suppresses NF-kB signaling and thereby sensitized HCC cells to the doxorubicin-induced apoptosis by inhibiting the expression of TAk1 and TAB3.

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [50]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-221 can activate the p53/mdm2 axis by inhibiting MDM2 and, in turn, p53 activation contributes to miR-221 enhanced expression. Moreover, by modulating the p53 axis, miR-221 impacts cell-cycle progression and apoptotic response to doxorubicin in hepatocellular carcinoma-derived cell lines.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [51]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-101-mediated EZH2 silencing sensitized hepatoblastoma cells to 5-FU- and doxorubicin-induced apoptosis, whereas antagomiR-mediated downregulation of endogenous miR-101 reversed the pro-apoptotic effect.

Key Molecule: Nuclear receptor subfamily 1 group I3 (NR1I3) [53]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Immunodeficient NCr nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell titer glo assay assay
• Mechanism Description: Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells.

Key Molecule: Extracellular matrix receptor III (CD44) [56]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: There is an inverse correlation between the expression of miR-199a-3p and CD44 protein. Transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin. Inhibition of CD44 in CD44+ HCC cell lines using antisense oligonucleotides increased apoptosis, enhanced chemosensitivity, reduced tumorigensis and invasion.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [57]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell invasion assay
• Mechanism Description: The mTOR pathway is activated by multiple extracellular signals, such as growth factors, nutrients, amino acids, hormones, and mitogens leading to the phosphorylation of the translational regulator, phospho-p70S6 kinase, which, in turn, regulates cell proliferation, regulates protein synthesis, and allows progression from the G1 to the S phase of the cell cycle. There is an inverse correlation linking miR-199a-3p and mTOR. miR-199a-3p restoration blocks the G1-S transition of the cell cycle, impairs invasion capability, and sensitizes HCC cells to doxorubicin challenge.

Key Molecule: Cyclin-G1 (CCNG1) [58]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V/propidium iodide detection kit
• Mechanism Description: miR-122 enforced expression, as well as cyclin G1 silencing, leads to increased p53 protein stability and transcriptional activity and reduced invasion capability of HCC-derived cell lines, miR-122, through down-regulation of cyclin G1, can trigger apoptosis and increase sensitivity of HCC-derived cells to doxorubicin.

Key Molecule: Fatty acid synthase (FASN) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Isocitrate dehydrogenase NAD 3 alpha (IDH3A) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Solute carrier family 16 member 1 (SLC16A1) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Solute carrier family 16 member 3 (SLC16A3) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit (SDHB) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin was able to induce SDH expression and repress the IDH3a in HepG2 cells both in a normal or elevated level of glucose. Such changes in SDH and IDH3a levels can bring a reduction in the succinate accumulation and hindering the succinate-HIF-1alpha axis. The augmented expression of HIF-1alpha in high glucose conditions was resisted by curcumin. HIF-1alpha is known for metabolic regulation in malignant cells, their hyperglycolytic behavior, and the onset of chemoresistance. HIF-1 exerts protumor effects through the upregulated expression of enzymes and transporters favoring the hyperglycolytic and therapy-resistant phenotype.

Key Molecule: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit (SDHB) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Epirubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27b [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-G1 (CCNG1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Erdafitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 4 (FGFR4) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V550L
• Resistant Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Key Molecule: Fibroblast growth factor receptor 4 (FGFR4) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V550E
• Resistant Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Key Molecule: Fibroblast growth factor receptor 4 (FGFR4) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V550L
• Resistant Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Key Molecule: Fibroblast growth factor receptor 4 (FGFR4) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V550E
• Resistant Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Etoposide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-196b [61]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• 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: c-Myc signaling pathway; Activation; hsa05230
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-196b overexpression decreased IGF2BP1 RNA expression and protein level. The IGF2BP1 down-regulation by either miR-196b or IGF2BP1 siRNA led to an increase in apoptosis and a decrease in cell viability and proliferation in normal culture conditions. However, IGF2BP1 silencing did not modify the chemoresistance induced by hypoxia, probably because it is not the only target of miR-196b involved in the regulation of apoptosis.

Key Molecule: hsa-mir-27b [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: hsa-mir-23a [62]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-23a could significantly potentiate the in vitro and in vivo anti-tumor effect of etoposide; miR-23a could directly bind to 3'untranslated region of TOP1 mRNA, and suppress the corresponding protein expression and inhibition of miR-23a further arguments the expression of TOP1. Suppression of TOP1 expression by miR-23a results in reduction of overall intracellular topoisomerase activity when the cells are exposed to etoposide, which in consequence enhances drug response of HCC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [61]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• 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: c-Myc signaling pathway; Activation; hsa05230
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-196b overexpression decreased IGF2BP1 RNA expression and protein level. The IGF2BP1 down-regulation by either miR-196b or IGF2BP1 siRNA led to an increase in apoptosis and a decrease in cell viability and proliferation in normal culture conditions. However, IGF2BP1 silencing did not modify the chemoresistance induced by hypoxia, probably because it is not the only target of miR-196b involved in the regulation of apoptosis.

Key Molecule: Cyclin-G1 (CCNG1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: DNA topoisomerase 1 (TOP1) [62]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-23a could significantly potentiate the in vitro and in vivo anti-tumor effect of etoposide; miR-23a could directly bind to 3'untranslated region of TOP1 mRNA, and suppress the corresponding protein expression and inhibition of miR-23a further arguments the expression of TOP1. Suppression of TOP1 expression by miR-23a results in reduction of overall intracellular topoisomerase activity when the cells are exposed to etoposide, which in consequence enhances drug response of HCC cells.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-33a [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Colorectal neoplasia differentially expressed (CRNDE) [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: hsa-miR-200a-3p [63]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; Colony forming assay
• Mechanism Description: miR200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. HULC inhibits the expression and activity of miR6825-5p, miR6845-5p and miR6886-3p.

Key Molecule: hsa-miR-6825-5p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6845-5p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6886-3p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-mir-503 [65]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5 fluorouracil by targeting EIF4E.

Key Molecule: hsa-mir-122 [66]

• Resistant Disease: Hepatic carcinoma [ICD-11: 2C12.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR122/PCDH20/AKT/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: MHCC97 cells; Liver; Homo sapiens (Human); CVCL_4971
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; RT-qPCR
• Experiment for Drug Resistance: MTT assay; CellTiter 96 Aqueous One Solution cell proliferation assay
• Mechanism Description: Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma. Rescue of PCDH20 expression in miR122-expressing cells decreases Akt and mTOR phosphorylation, re-sensitizing hepatocellular carcinoma cell to 5-fluorouracil induced apoptosis.

Key Molecule: hsa-mir-21 [67]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Phosphatase and tensin homolog (PTEN) [68]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: Bel/5-FU cells; Liver; Homo sapiens (Human); CVCL_5493
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Wound healing assay; Transwell assay
• Mechanism Description: Over-expression of miR-32-5p activated the PI3k/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition.

Key Molecule: hsa-miR-32-5p [68]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: Bel/5-FU cells; Liver; Homo sapiens (Human); CVCL_5493
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Wound healing assay; Transwell assay
• Mechanism Description: Over-expression of miR-32-5p activated the PI3k/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition.

Key Molecule: Small nucleolar RNA host gene 6 (SNHG6) [69]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: HCC-LM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8; Flow cytometry assay; EdU assay
• Mechanism Description: Ectopic expression of SNHG6-003 in HCC cells promoted cell proliferation and induced drug resistance, whereas SNHG6-003 knockdown promoted apoptosis. Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-beta-activated kinase 1 (TAk1). Importantly, expression analysis revealed that both SNHG6-003 and TAk1 were upregulated in human cancers, exhibiting a co-expression pattern. In HCC patients, high expression of SNHG6-003 closely correlated with tumor progression and shorter survival.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: High mobility group protein HMGI-C (HMGA2) [10]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Luciferase activity assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Dual specificity protein phosphatase 6 (DUSP6) [63]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; Colony forming assay
• Mechanism Description: miR200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression.

Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22) [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: Eukaryotic translation initiation factor 4E (EIF4E) [65]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5 fluorouracil by targeting EIF4E.

Key Molecule: Protocadherin-20 (PCDH20) [66]

• Resistant Disease: Hepatic carcinoma [ICD-11: 2C12.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR122/PCDH20/AKT/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: MHCC97 cells; Liver; Homo sapiens (Human); CVCL_4971
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; CellTiter 96 Aqueous One Solution cell proliferation assay
• Mechanism Description: Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma. Rescue of PCDH20 expression in miR122-expressing cells decreases Akt and mTOR phosphorylation, re-sensitizing hepatocellular carcinoma cell to 5-fluorouracil induced apoptosis.

Key Molecule: Nuclear receptor subfamily 2 group C2 (NR2C2) [69]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: HCC-LM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8; Flow cytometry assay; EdU assay
• Mechanism Description: Ectopic expression of SNHG6-003 in HCC cells promoted cell proliferation and induced drug resistance, whereas SNHG6-003 knockdown promoted apoptosis. Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-beta-activated kinase 1 (TAk1). Importantly, expression analysis revealed that both SNHG6-003 and TAk1 were upregulated in human cancers, exhibiting a co-expression pattern. In HCC patients, high expression of SNHG6-003 closely correlated with tumor progression and shorter survival.

Key Molecule: Programmed cell death protein 4 (PDCD4) [67]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Key Molecule: Phosphatase and tensin homolog (PTEN) [67]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-379 [40]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: Long non-protein coding RNA 607 (LINC00607) [42]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Real-time RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Key Molecule: Long non-protein coding RNA (KRAL) [70]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: hsa-mir-141 [70]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: Long non-protein coding RNA (KRAL) [70]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: hsa-mir-183 [71]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR183/IDH2/SOCS6/HIF1alpha feedback loop signaling pathway; Regulation; hsa05206
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: IDH2 knockdown resulted in significantly increased HIF-1alpha expression in both BEL-7402 and BEL-7402/5-FU cells. knockdown of SOCS6 had similar but stronger effect as miR-183 in promoting MRP2, P-gp, p-STAT3 and HIF-1alpha expression in BEL-7402 cells, while SOCS6 overexpression also showed similar but stronger effect as miR-183 inhibition in reducing MRP2, P-gp, p-STAT3 and HIF-1alpha levels in BEL-7402/5-FU cells. Both SOCS6 overexpression and miR-183 knockdown significantly increased the sensitivity of BEL-7402/5-FU cells to 5-FU. miR-183 overexpression partly abrogated the effect of SOCS6 in enhancing 5-FU sensitivity.

Key Molecule: hsa-mir-133a [23]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-miR-326 [23]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-let-7b [72]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Let-7b increased 5 FU sensitivity by repressing Bcl xl expression in HCC cells.

Key Molecule: hsa-mir-125b [73]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: THLE-2 cells; Liver; Homo sapiens (Human); CVCL_3803
• In Vitro Model: THLE-3 cells; Liver; Homo sapiens (Human); CVCL_3804
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Compared with 5-FU-sensitive cells, 5-FU-resistant cells exhibited reduced expression levels of miR-125b, and transfection of pre-miR-125b into liver cancer cells resulted in an increased sensitivity of 5-FU-resistant cells to 5-FU. Since drug resistance is a phenotype of malignant cancer cells, the finding that miR-125b expression levels are negatively correlated with 5-FU resistance in HCC cells is consistent with the reported functions of miR-125b. In addition, 5-FU-resistant cells exhibited higher glucose metabolic activity than 5-FU-sensitive cells, and miR-125 was identified to downregulate glucose metabolism by directly targeting Hk II. These results identified miR-125b as a tumor suppressor-like microRNA, which has great potential as a diagnostic and prognostic biomarker.

Key Molecule: hsa-let-7g [74]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Inhibition; hsa04110
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Let-7g microRNA contributed to an increase of 5-Fu-induced cell cycle inhibit in human hepatoma cell and sensitized cells to 5-Fu, leading to increased the effectiveness of the drug in treating hepatoma cancer.

Key Molecule: hsa-mir-101 [51]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-101-mediated EZH2 silencing sensitized hepatoblastoma cells to 5-FU- and doxorubicin-induced apoptosis, whereas antagomiR-mediated downregulation of endogenous miR-101 reversed the pro-apoptotic effect.

Key Molecule: hsa-mir-200b [75]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: hsa-mir-200c [75]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: hsa-miR-193a-3p [76]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: FOCUS cells; Liver; Homo sapiens (Human); CVCL_7955
• In Vitro Model: YY-8103 cells; Liver; Homo sapiens (Human); CVCL_WY40
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression.

Key Molecule: hsa-mir-195 [77]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-195 antisense oligonucleotide induced drug resistance in BEL-7402/5-FU cells. miR-195 overexpression repressed Bcl-w protein level. miR-195, one of the down-regulated miRNAs in BEL-7402/5-FU cells, was demonstrated to play a role in the development of drug resistance in hepatocellular carcinoma cells by targeting the antiapoptotic gene, Bcl-w.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [78]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Boyden chamber assay; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [78]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Phosphorylation; Down-regulation
• Sensitive Drug: Fluorouracil
• 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
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Boyden chamber assay; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [78]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Phosphorylation; Down-regulation
• Sensitive Drug: Fluorouracil
• 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
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [40]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: Cellular tumor antigen p53 (TP53) [42]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Key Molecule: Kelch-like ECH-associated protein 1 (KEAP1) [70]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [23], [72]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; MTT assay
• Mechanism Description: Let-7b increased 5 FU sensitivity by repressing Bcl xl expression in HCC cells. And miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: Suppressor of cytokine signaling 6 (SOCS6) [71]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR183/IDH2/SOCS6/HIF1alpha feedback loop signaling pathway; Regulation; hsa05206
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: IDH2 knockdown resulted in significantly increased HIF-1alpha expression in both BEL-7402 and BEL-7402/5-FU cells. knockdown of SOCS6 had similar but stronger effect as miR-183 in promoting MRP2, P-gp, p-STAT3 and HIF-1alpha expression in BEL-7402 cells, while SOCS6 overexpression also showed similar but stronger effect as miR-183 inhibition in reducing MRP2, P-gp, p-STAT3 and HIF-1alpha levels in BEL-7402/5-FU cells. Both SOCS6 overexpression and miR-183 knockdown significantly increased the sensitivity of BEL-7402/5-FU cells to 5-FU. miR-183 overexpression partly abrogated the effect of SOCS6 in enhancing 5-FU sensitivity.

Key Molecule: Hexokinase-2 (HK2) [73]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: THLE-2 cells; Liver; Homo sapiens (Human); CVCL_3803
• In Vitro Model: THLE-3 cells; Liver; Homo sapiens (Human); CVCL_3804
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Compared with 5-FU-sensitive cells, 5-FU-resistant cells exhibited reduced expression levels of miR-125b, and transfection of pre-miR-125b into liver cancer cells resulted in an increased sensitivity of 5-FU-resistant cells to 5-FU. Since drug resistance is a phenotype of malignant cancer cells, the finding that miR-125b expression levels are negatively correlated with 5-FU resistance in HCC cells is consistent with the reported functions of miR-125b. In addition, 5-FU-resistant cells exhibited higher glucose metabolic activity than 5-FU-sensitive cells, and miR-125 was identified to downregulate glucose metabolism by directly targeting Hk II. These results identified miR-125b as a tumor suppressor-like microRNA, which has great potential as a diagnostic and prognostic biomarker.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [74]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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 cycle; Activation; hsa04110
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Let-7g microRNA contributed to an increase of 5-Fu-induced cell cycle inhibit in human hepatoma cell and sensitized cells to 5-Fu, leading to increased the effectiveness of the drug in treating hepatoma cancer.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [51]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-101-mediated EZH2 silencing sensitized hepatoblastoma cells to 5-FU- and doxorubicin-induced apoptosis, whereas antagomiR-mediated downregulation of endogenous miR-101 reversed the pro-apoptotic effect.

Key Molecule: Rho-associated protein kinase 2 (ROCK2) [75]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: Polycomb protein SUZ12 (SUZ12) [75]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: Transcription factor E2F1 (E2F1) [76]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: FOCUS cells; Liver; Homo sapiens (Human); CVCL_7955
• In Vitro Model: YY-8103 cells; Liver; Homo sapiens (Human); CVCL_WY40
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression.

Key Molecule: Serine/arginine-rich splicing factor 2 (SRSF2) [76]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: FOCUS cells; Liver; Homo sapiens (Human); CVCL_7955
• In Vitro Model: YY-8103 cells; Liver; Homo sapiens (Human); CVCL_WY40
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [77]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-195 antisense oligonucleotide induced drug resistance in BEL-7402/5-FU cells. miR-195 overexpression repressed Bcl-w protein level. miR-195, one of the down-regulated miRNAs in BEL-7402/5-FU cells, was demonstrated to play a role in the development of drug resistance in hepatocellular carcinoma cells by targeting the antiapoptotic gene, Bcl-w.

Gefitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gefitinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27b [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gefitinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-G1 (CCNG1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gefitinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-130a-3p [79]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCLP-1 cells; Liver; Homo sapiens (Human); CVCL_0205
• In Vitro Model: MzChA-1 cells; Liver; Homo sapiens (Human); CVCL_6932
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Transfection of miR130a-3p mimic suppressed the expression of PPARG and increased gemcitabine resistance.

Key Molecule: Peroxisome proliferator-activated receptor gamma (PPARG) [79]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCLP-1 cells; Liver; Homo sapiens (Human); CVCL_0205
• In Vitro Model: MzChA-1 cells; Liver; Homo sapiens (Human); CVCL_6932
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Transfection of miR130a-3p mimic suppressed the expression of PPARG and increased gemcitabine resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-205 [80]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HuCCT1 cells; Bile duct; Homo sapiens (Human); CVCL_0324
• In Vitro Model: HuH28 cells; Bile duct; Homo sapiens (Human); CVCL_2955
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-205 could conferred Gem sensitivity to innately Gem-resistant CCA cells.

Key Molecule: hsa-mir-221 [80]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HuCCT1 cells; Bile duct; Homo sapiens (Human); CVCL_0324
• In Vitro Model: HuH28 cells; Bile duct; Homo sapiens (Human); CVCL_2955
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-221 was downregulated in Gem-resistant HuH28 cells, and that it acted as a potent enhancer of Gem sensitivity, at least partly, by downregulating PIk3R1 expression.

Key Molecule: hsa-mir-29b [80]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HuCCT1 cells; Bile duct; Homo sapiens (Human); CVCL_0324
• In Vitro Model: HuH28 cells; Bile duct; Homo sapiens (Human); CVCL_2955
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Two miR-29b target genes, PIk3R1 and MMP-2, that are, at least partly, responsible for the resistance of CCA Gem treatment. PIk3R1 encodes phosphoinositide 3-kinase (PI3k) regulatory subunit designated p85 alpha; p85 alpha is regarded as integrator of multiple signaling pathways that together promote cell proliferation, cell survival, and carcinogenesis.

Key Molecule: hsa-mir-200b [81]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: KMCH-1 cells; Gallbladder; Homo sapiens (Human); CVCL_7970
• In Vitro Model: Mz-ChA-1 cells; Gallbladder; Homo sapiens (Human); CVCL_6932
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: PTPN12 can bind and dephosphorylate the product ofoncogenes such as c-Abl or Src and inactivate the Raspathway. Thus, deregulation of PTPN12 expressionmay contribute to tumor cell survival and oncogenesis. In cells transfected with anti-miR-200b, PTPN12 ex-pression was increased to 132.2%+/-7.2% of controlafter 48 hours and 147.3%+/-12.8% of control after 72hours. Moreover, inhibition of miR-200b significantlyreduced the tyrosine phosphorylation of a downstreamtarget Src, a key mediator of tumor cell proliferation anddifferentiation.

Key Molecule: hsa-mir-21 [81]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: KMCH-1 cells; Gallbladder; Homo sapiens (Human); CVCL_7970
• In Vitro Model: Mz-ChA-1 cells; Gallbladder; Homo sapiens (Human); CVCL_6932
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-21, miR-141, and miR-200b werehighly over-expressed in malignant cholangiocytes. Inhibi-tion of miR-21 and miR-200b increased sensitivity to gem-citabine, whereas inhibition of miR-141 decreased cellgrowth. miR-21 modulates gemcitabine-induced apo-ptosis by phosphatase and tensin homolog deleted onchromosome 10 (PTEN) -dependent activation of PI 3-ki-nase signaling.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Collagenase 72 kDa type IV collagenase (MMP2) [80]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HuCCT1 cells; Bile duct; Homo sapiens (Human); CVCL_0324
• In Vitro Model: HuH28 cells; Bile duct; Homo sapiens (Human); CVCL_2955
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Two miR-29b target genes, PIk3R1 and MMP-2, that are, at least partly, responsible for the resistance of CCA Gem treatment. PIk3R1 encodes phosphoinositide 3-kinase (PI3k) regulatory subunit designated p85 alpha; p85 alpha is regarded as integrator of multiple signaling pathways that together promote cell proliferation, cell survival, and carcinogenesis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1) [80]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HuCCT1 cells; Bile duct; Homo sapiens (Human); CVCL_0324
• In Vitro Model: HuH28 cells; Bile duct; Homo sapiens (Human); CVCL_2955
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Two miR-29b target genes, PIk3R1 and MMP-2, that are, at least partly, responsible for the resistance of CCA Gem treatment. PIk3R1 encodes phosphoinositide 3-kinase (PI3k) regulatory subunit designated p85 alpha; p85 alpha is regarded as integrator of multiple signaling pathways that together promote cell proliferation, cell survival, and carcinogenesis.

Key Molecule: Phosphatase and tensin homolog (PTEN) [81]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: KMCH-1 cells; Gallbladder; Homo sapiens (Human); CVCL_7970
• In Vitro Model: Mz-ChA-1 cells; Gallbladder; Homo sapiens (Human); CVCL_6932
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-21, miR-141, and miR-200b werehighly over-expressed in malignant cholangiocytes. Inhibi-tion of miR-21 and miR-200b increased sensitivity to gem-citabine, whereas inhibition of miR-141 decreased cellgrowth. miR-21 modulates gemcitabine-induced apo-ptosis by phosphatase and tensin homolog deleted onchromosome 10 (PTEN) -dependent activation of PI 3-ki-nase signaling.

Key Molecule: Tyrosine-protein phosphatase non-receptor type 12 (PTPN12) [81]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: H69 cells; Lung; Homo sapiens (Human); CVCL_8121
• In Vitro Model: KMCH-1 cells; Gallbladder; Homo sapiens (Human); CVCL_7970
• In Vitro Model: Mz-ChA-1 cells; Gallbladder; Homo sapiens (Human); CVCL_6932
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: PTPN12 can bind and dephosphorylate the product ofoncogenes such as c-Abl or Src and inactivate the Raspathway. Thus, deregulation of PTPN12 expressionmay contribute to tumor cell survival and oncogenesis. In cells transfected with anti-miR-200b, PTPN12 ex-pression was increased to 132.2%+/-7.2% of controlafter 48 hours and 147.3%+/-12.8% of control after 72hours. Moreover, inhibition of miR-200b significantlyreduced the tyrosine phosphorylation of a downstreamtarget Src, a key mediator of tumor cell proliferation anddifferentiation.

IFN-alpha

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-146a [82]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: IFN-alpha
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta signaling pathway; Activation; hsa04310
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-146a confers resistance to IFN-alpha in HCC cells by inhibiting apoptosis through SMAD4.

Key Molecule: hsa-mir-21 [67]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: IFN-alpha
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4) [82]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: IFN-alpha
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta signaling pathway; Activation; hsa04310
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-146a confers resistance to IFN-alpha in HCC cells by inhibiting apoptosis through SMAD4.

Key Molecule: Programmed cell death protein 4 (PDCD4) [67]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: IFN-alpha
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Key Molecule: Phosphatase and tensin homolog (PTEN) [67]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: IFN-alpha
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA 607 (LINC00607) [42]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: IFN-alpha
• 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: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Real-time RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [42]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: IFN-alpha
• 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: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Infigratinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 1 (FGFR1) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Structural variation; Amplification
• Resistant Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signalling pathway; Activation; hsa04020
• Cell Pathway Regulation: ERK/MAPK signaling pathway; Activation; hsa04210
• In Vitro Model: DMS114 cells; Lung; Homo sapiens (Human); CVCL_1174
• Mechanism Description: Upregulation of the MET signalling pathway leading to re-activation of the ERK/MAPK pathway was observed in conjunction with the development of resistance to infigratinib in FGFR1-amplified DMS114 lung cancer cells.

Key Molecule: Fibroblast growth factor receptor 1 (FGFR1) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Structural variation; Amplification
• Resistant Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signalling pathway; Activation; hsa04020
• Cell Pathway Regulation: ERK/MAPK signaling pathway; Activation; hsa04210
• In Vitro Model: DMS114 cells; Lung; Homo sapiens (Human); CVCL_1174
• Mechanism Description: Upregulation of the MET signalling pathway leading to re-activation of the ERK/MAPK pathway was observed in conjunction with the development of resistance to infigratinib in FGFR1-amplified DMS114 lung cancer cells.

Lamivudine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-let-7a [33]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Lamivudine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Caspase-3 is the key executioner caspase in apoptosis. Ectopic expression of let-7adecreased the luciferase activity of a reporter constructcontaining the 30untranslated region of caspase-3. Enforced let-7aexpression increased the resistance in A431 cells andHepG2 cells to apoptosis induced by therapeutic drugs suchas interferon-gamma, doxorubicin and paclitaxel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Caspase-3 (CASP3) [33]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Lamivudine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Caspase-3 is the key executioner caspase in apoptosis. Ectopic expression of let-7adecreased the luciferase activity of a reporter constructcontaining the 30untranslated region of caspase-3. Enforced let-7aexpression increased the resistance in A431 cells andHepG2 cells to apoptosis induced by therapeutic drugs suchas interferon-gamma, doxorubicin and paclitaxel.

Lenvatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dual specificity phosphatase 9 (DUSP9) [83]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Lenvatinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: FOXO3 signaling pathway; Inhibition; hsa04068
• In Vivo Model: Xenograft-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Quantitative RT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance.

Key Molecule: Neurofibromin (NF1) [83]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Lenvatinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: FOXO3 signaling pathway; Inhibition; hsa04068
• In Vivo Model: Xenograft-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Quantitative RT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance.

Methotrexate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glyceraldehyde-3-phosphate dehydrogenase 1 (GAPDH) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Hexokinase-2 (HK2) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Isocitrate dehydrogenase NAD 3 alpha (IDH3A) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Solute carrier family 16 member 1 (SLC16A1) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Solute carrier family 16 member 3 (SLC16A3) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Phosphofructo-1-kinase isozyme B (PFKB) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Pyruvate kinase M2 (PKM) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HkII, PFk1, GAPDH, PkM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death.

Key Molecule: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit (SDHB) [59]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Curcumin was able to induce SDH expression and repress the IDH3a in HepG2 cells both in a normal or elevated level of glucose. Such changes in SDH and IDH3a levels can bring a reduction in the succinate accumulation and hindering the succinate-HIF-1alpha axis. The augmented expression of HIF-1alpha in high glucose conditions was resisted by curcumin. HIF-1alpha is known for metabolic regulation in malignant cells, their hyperglycolytic behavior, and the onset of chemoresistance. HIF-1 exerts protumor effects through the upregulated expression of enzymes and transporters favoring the hyperglycolytic and therapy-resistant phenotype.

Mitomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-146a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. HULC inhibits the expression and activity of miR6825-5p, miR6845-5p and miR6886-3p.

Key Molecule: hsa-miR-6825-5p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6845-5p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6886-3p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-7-5p [84]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR7-5p/ABCC1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.

Key Molecule: KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) [84]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR7-5p/ABCC1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.

Key Molecule: NR2F1 antisense RNA 1 (NR2F1-AS1) [85]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: NR2F1/AS1/miR363/ABCC1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: Both NR2F1-AS1 and ABCC1 were up-regulated in oxaliplatin-resistant HCC cells,and miR-363 expression was increased in Huh7/OXA and HepG2/OXA cells transfected with NR2F1-AS1 siRNA compared to empty vector-transfected cells.

Key Molecule: hsa-mir-363 [85]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NR2F1/AS1/miR363/ABCC1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: Both NR2F1-AS1 and ABCC1 were up-regulated in oxaliplatin-resistant HCC cells,and miR-363 expression was increased in Huh7/OXA and HepG2/OXA cells transfected with NR2F1-AS1 siRNA compared to empty vector-transfected cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [84]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: miR7-5p/ABCC1 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22) [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-122 [86]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-122 inhibits MDR1 expression via suppression of Wnt/beta-catenin pathway, thereby enhancing HCC sensitivity to OXA.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [86]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-122 inhibits MDR1 expression via suppression of Wnt/beta-catenin pathway, thereby enhancing HCC sensitivity to OXA.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-16 [87]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Silencing the expression of miR-16 induced the chemoresistance in HCC by target IkBkB via NF-kB signaling pathway.

Key Molecule: hsa-let-7a [33]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Caspase-3 is the key executioner caspase in apoptosis. Ectopic expression of let-7adecreased the luciferase activity of a reporter constructcontaining the 30untranslated region of caspase-3. Enforced let-7aexpression increased the resistance in A431 cells andHepG2 cells to apoptosis induced by therapeutic drugs suchas interferon-gamma, doxorubicin and paclitaxel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: I-kappa-B-kinase beta (IKKB) [87]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Silencing the expression of miR-16 induced the chemoresistance in HCC by target IkBkB via NF-kB signaling pathway.

Key Molecule: Caspase-3 (CASP3) [33]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Caspase-3 is the key executioner caspase in apoptosis. Ectopic expression of let-7adecreased the luciferase activity of a reporter constructcontaining the 30untranslated region of caspase-3. Enforced let-7aexpression increased the resistance in A431 cells andHepG2 cells to apoptosis induced by therapeutic drugs suchas interferon-gamma, doxorubicin and paclitaxel.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-379 [40]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: hsa-mir-335 [88]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR335/SIAH2/HDAC3 signaling pathway; Regulation; hsa05206
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue exclusion assay; Transwell assay
• Mechanism Description: miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

Key Molecule: hsa-mir-223 [54]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HCC3 cells; Liver; Homo sapiens (Human); CVCL_0C57
• In Vitro Model: LM-6 cells; Liver; Homo sapiens (Human); CVCL_7680
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-223 targeted ABCB1 3'UTR directly, and miR-223 down-regulated ABCB1 at both mRNA and protein levels. The over-expression of miR-223 increased the HCC cellsensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencingof ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [54]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HCC3 cells; Liver; Homo sapiens (Human); CVCL_0C57
• In Vitro Model: LM-6 cells; Liver; Homo sapiens (Human); CVCL_7680
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-223 targeted ABCB1 3'UTR directly, and miR-223 down-regulated ABCB1 at both mRNA and protein levels. The over-expression of miR-223 increased the HCC cellsensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencingof ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [40]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: E3 ubiquitin-protein ligase SIAH2 (SIAH2) [88]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR335/SIAH2/HDAC3 signaling pathway; Regulation; hsa05206
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay; Transwell assay
• Mechanism Description: miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

Pemigatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [89]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Function; Inhibition
• Resistant Drug: Pemigatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Genomic profiling assay
• Mechanism Description: The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Pemigatinib is a selective, potent, oral, competitive inhibitor of FGFR1, 2, and 3 that inhibits receptor autophosphorylation and subsequent activation of FGF/FGFR-mediated signaling networks, leading to an inhibition of tumor cell growth in FGFR-driven cancers.

Pirarubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. HULC inhibits the expression and activity of miR6825-5p, miR6845-5p and miR6886-3p.

Key Molecule: hsa-miR-6825-5p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6845-5p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6886-3p [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22) [64]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Janus kinase 1 (JAK-1) [90]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Missense mutation; p.S703I (c.2108G>T)
• Sensitive Drug: Ruxolitinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: JAK1 cells; N.A.; .; N.A.
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Tumor volume measurement assay

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-374b [91]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PKM2 mediated glycolysis signaling pathway; Activation; hsa05230
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-374b/hnRNPA1/PkM2 axis functions as an important mechanism in sorafenib resistance, with sorafenib-induced miR-374b downregulation and subsequently elevated glycolysis.

Key Molecule: hsa-miR-613 [11]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: SOX9 signaling pathway; Activation; hsa04024
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.

Key Molecule: Small nucleolar RNA host gene 1 (SNHG1) [92]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpressed SNHG1 contributes to sorafenib resistance by activating the Akt pathway via regulating SLC3A2.

Key Molecule: hsa-mir-21 [92]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [93]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: c-Met/AKT signaling pathway; Inhibition; hsa01521
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA NEAT1 mediates Sora resistance of HCC cells by suppressing miR-335 expression, and disinhibition on c-Met-Akt signaling pathway.

Key Molecule: hsa-mir-335 [93]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: c-Met/AKT signaling pathway; Inhibition; hsa01521
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Dual-luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA NEAT1 mediates Sora resistance of HCC cells by suppressing miR-335 expression, and disinhibition on c-Met-Akt signaling pathway.

Key Molecule: hsa-mir-494 [94]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Molecule Alteration: qPCR; RT-sqPCR
• Experiment for Drug Resistance: Cell viability assay; Caspase-3/7 activity assay; WB analysis
• Mechanism Description: miR494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines, by targeting p27, pten, and puma.

Key Molecule: Homeobox protein Hox-A13 (HOXA13) [95]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Soft Agar Colony Assay; xCELLigence assay
• Mechanism Description: Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro.

Key Molecule: hsa-mir-221 [96]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Caspase 3/7 activity assay; Cell-titer-Glo assay; Flow cytometry assay
• Mechanism Description: In hepatocellular carcinoma miR221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis.

Key Molecule: PCBP2 overlapping transcript 1 (PCBP2-OT1) [97]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RASAL1 signaling pathway; Inhibition; hsa04014
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long non-coding RNA TUC338 is functionally involved in sorafenib-sensitized hepatocarcinoma cells by targeting RASAL1. knockdown of TUC338 was accompanied with increased expression of RASAL1 in HCC cell line with increased proliferation and invasion ability, knockdown of TUC338 could activate the RASAL1 pathway and inhibit tumor growth genes by directly targeting RASAL1 3'-UTR.

Key Molecule: hsa-miR-19a-3p [98]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-19a-3p induces sorafenib resistance through downregulation of PTEN expression.

Key Molecule: hsa-mir-222 [99]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR 222 facilitate sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma.

Key Molecule: hsa-mir-216a [100]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.

Key Molecule: hsa-mir-217 [100]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.

Key Molecule: hsa-mir-375 [101]

• Resistant Disease: Hepatic carcinoma [ICD-11: 2C12.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: Huh1 cells; Liver; Homo sapiens (Human); CVCL_2956
• In Vivo Model: BALB/c athymic nude mice; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting analysis; ELISA assay
• Mechanism Description: The expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. The expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1).

Key Molecule: hsa-mir-375 [101]

• Resistant Disease: Hepatic carcinoma [ICD-11: 2C12.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: Huh1 cells; Liver; Homo sapiens (Human); CVCL_2956
• In Vivo Model: BALB/c athymic nude mice; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting analysis; ELISA assay
• Mechanism Description: The expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. The expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lymphocyte activation antigen 4F2 (SLC3A2) [92]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpressed SNHG1 contributes to sorafenib resistance by activating the Akt pathway via regulating SLC3A2.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [35]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [35]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Very low density lipoprotein receptor (VLDLR) [35]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Key Molecule: Very low density lipoprotein receptor (VLDLR) [35]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) [91]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PKM2 mediated glycolysis signaling pathway; Activation; hsa05230
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-374b/hnRNPA1/PkM2 axis functions as an important mechanism in sorafenib resistance, with sorafenib-induced miR-374b downregulation and subsequently elevated glycolysis.

Key Molecule: Pyruvate kinase M2 (PKM) [91]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PKM2 mediated glycolysis signaling pathway; Activation; hsa05230
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-374b/hnRNPA1/PkM2 axis functions as an important mechanism in sorafenib resistance, with sorafenib-induced miR-374b downregulation and subsequently elevated glycolysis.

Key Molecule: Transcription factor SOX-9 (SOX9) [11]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: SOX9 signaling pathway; Activation; hsa04024
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.

Key Molecule: RAC serine/threonine-protein kinase (AKT) [92]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [92]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.

Key Molecule: Hepatocyte growth factor receptor (MET) [93]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: c-Met/AKT signaling pathway; Inhibition; hsa01521
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual-luciferase reporter assay; Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA NEAT1 suppresses sorafenib sensitivity of hepatocellular carcinoma cells via regulating miR-335-c-Met.

Key Molecule: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [94]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Molecule Alteration: Western blot analysis; Luciferase activity assay
• Experiment for Drug Resistance: Cell viability assay; Caspase-3/7 activity assay; WB analysis
• Mechanism Description: miR494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines, by targeting p27, pten, and puma.

Key Molecule: Phosphatase and tensin homolog (PTEN) [94]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Molecule Alteration: Western blot analysis; Luciferase activity assay
• Experiment for Drug Resistance: Cell viability assay; Caspase-3/7 activity assay; WB analysis
• Mechanism Description: miR494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines, by targeting p27, pten, and puma.

Key Molecule: Bcl-2-binding component 3 (BBC3) [94]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Molecule Alteration: Western blot analysis; Luciferase activity assay
• Experiment for Drug Resistance: Cell viability assay; Caspase-3/7 activity assay; WB analysis
• Mechanism Description: miR494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines, by targeting p27, pten, and puma.

Key Molecule: Caspase-3 (CASP3) [96]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase 3/7 activity assay; Cell-titer-Glo assay; Flow cytometry assay
• Mechanism Description: In hepatocellular carcinoma miR221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis.

Key Molecule: RasGAP-activating-like protein 1 (RASAL1) [97]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: RASAL1 signaling pathway; Inhibition; hsa04014
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long non-coding RNA TUC338 is functionally involved in sorafenib-sensitized hepatocarcinoma cells by targeting RASAL1. knockdown of TUC338 was accompanied with increased expression of RASAL1 in HCC cell line with increased proliferation and invasion ability, knockdown of TUC338 could activate the RASAL1 pathway and inhibit tumor growth genes by directly targeting RASAL1 3'-UTR.

Key Molecule: Phosphatase and tensin homolog (PTEN) [98]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-19a-3p induces sorafenib resistance through downregulation of PTEN expression.

Key Molecule: Phosphatase and tensin homolog (PTEN) [100]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.

Key Molecule: Mothers against decapentaplegic homolog 7 (SMAD7) [100]

• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: BEL-7404 cells; Liver; Homo sapiens (Human); CVCL_6568
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-378 [102]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRbeta and c Raf. Sorafenib can suppress tumor growth through the inhibition of multiple tyrosine kinases, including VEGFR, PDGFRbeta and c-Raf.

Key Molecule: hsa-mir-137 [103]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: Huh7-R cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Wound healing assay; Anoikis assays
• Mechanism Description: Upregulation of miR137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma.

Key Molecule: hsa-miR-367-3p [104]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: MDM2/AR-FkBP5/PHLPP signaling pathway; Regulation; hsa04115
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; hsa04010
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HA22T cells; Liver; Homo sapiens (Human); CVCL_7046
• In Vitro Model: SNU423 cells; Liver; Homo sapiens (Human); CVCL_0366
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: 3D Invasion Assay
• Mechanism Description: miR367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FkBP5 and PHLPP, thus dephosphorylating and inactivating AkT and ERk, to suppress the HCC cell invasion. miR367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FkBP5/PHLPP/(pAkT and pERk) signals to better suppress HCC metastasis.

Key Molecule: hsa-mir-122 [105]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: DEN-HCC mouse model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-122 overexpression increased sorafenib sensitivity in treated cells via downregulating SerpinB3 expression.

Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [106]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• 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: STAT3 signaling pathway; Inhibition; hsa04550
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vivo Model: NOD-SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Interference lncARSR suppressed liver CSCs expansion and the phosphorylation of the STAT3 molecule was evidently inactivated in both the SMMC7721 si-lncARSR and HCCLM3 si-lncARSR cells.

Key Molecule: hsa-mir-181a [107]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• 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: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Caspase 3/7 activity analysis; CCK8 assay
• Mechanism Description: miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.

Key Molecule: hsa-mir-122 [108]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• 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: RAS/RAF/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: T1115 cells; Liver; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance.

Key Molecule: hsa-mir-27b [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: hsa-miR-338-3p [109]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• 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: HIF signaling signaling pathway; Inhibition; hsa04066
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-338-3p inhibited HIF-1alpha 3'-UTR luciferase activity and HIF-1alpha protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1alpha overexpression rescued and HIF-1alpha knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1alpha. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1alpha.

Key Molecule: hsa-miR-425-3p [110]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 HCC cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; EdU assay
• Mechanism Description: miR-425-3p levels were induced by sorafenib incubation in HuH-7 cells-derived exosomes, and this cell line was more sensitive to cell death after incubation with the drug. The involvement of extracellular vesicles in modulating HCC response to sorafenib has recently emerged providing a potential novel strategy to interfere with HCC chemoresistance.

Key Molecule: hsa-mir-193b [111]

• Sensitive Disease: Hepatitis B virus-associated hepatocellular carcinoma [ICD-11: 2C12.7]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HBV infection in HCC cell lines enhances sorafenib resistance. HBV infection in HCC reduces miR-193b expression and increases Mcl-1 expression. miR-193b directly suppresses the expression of Mcl-1 through its 3'-UTRs. miR-193b facilitates sorafenib-induced apoptosis. miR-193b sensitizes HBV-associated HCC cell lines to sorafenib.

Key Molecule: hsa-mir-34 [112]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression.

Key Molecule: hsa-mir-122 [113]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Tumorigenic properties; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ADAM10 (a distintegrin and metalloprotease family), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and Sk-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1) [102]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRbeta and c Raf. Sorafenib can suppress tumor growth through the inhibition of multiple tyrosine kinases, including VEGFR, PDGFRbeta and c-Raf.

Key Molecule: Platelet-derived growth factor receptor beta (PDGFRB) [102]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRbeta and c Raf. Sorafenib can suppress tumor growth through the inhibition of multiple tyrosine kinases, including VEGFR, PDGFRbeta and c-Raf.

Key Molecule: Vascular endothelial growth factor (VEGFR) [102]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRbeta and c Raf. Sorafenib can suppress tumor growth through the inhibition of multiple tyrosine kinases, including VEGFR, PDGFRbeta and c-Raf.

Key Molecule: ADP/ATP translocase 2 (ANT2) [103]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: Huh7-R cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Wound healing assay; Anoikis assays
• Mechanism Description: Upregulation of miR137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma.

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [104]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MDM2/AR-FkBP5/PHLPP signaling pathway; Regulation; hsa04115
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; hsa04010
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HA22T cells; Liver; Homo sapiens (Human); CVCL_7046
• In Vitro Model: SNU423 cells; Liver; Homo sapiens (Human); CVCL_0366
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: 3D Invasion Assay
• Mechanism Description: miR367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FkBP5 and PHLPP, thus dephosphorylating and inactivating AkT and ERk, to suppress the HCC cell invasion. miR367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FkBP5/PHLPP/(pAkT and pERk) signals to better suppress HCC metastasis.

Key Molecule: Serpin B3 (SERPINB3) [105]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: DEN-HCC mouse model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-122 overexpression increased sorafenib sensitivity in treated cells via downregulating SerpinB3 expression.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [106]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Phosphorylation; Down-regulation
• Sensitive Drug: Sorafenib
• 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: STAT3 signaling pathway; Inhibition; hsa04550
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vivo Model: NOD-SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Interference lncARSR suppressed liver CSCs expansion and the phosphorylation of the STAT3 molecule was evidently inactivated in both the SMMC7721 si-lncARSR and HCCLM3 si-lncARSR cells.

Key Molecule: Ras association domain-containing protein 1 (RASSF1) [107]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Sorafenib
• 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: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase 3/7 activity analysis; CCK8 assay
• Mechanism Description: miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [108]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• 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: RAS/RAF/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: T1115 cells; Liver; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance.

Key Molecule: Cyclin-G1 (CCNG1) [24]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR27b/CCNG1/p53 signaling pathway; Regulation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-739 cells; Liver; Homo sapiens (Human); CVCL_5088
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.

Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A) [109]

• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• 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: HIF signaling signaling pathway; Inhibition; hsa04066
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-338-3p inhibited HIF-1alpha 3'-UTR luciferase activity and HIF-1alpha protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1alpha overexpression rescued and HIF-1alpha knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1alpha. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1alpha.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [111]

• Sensitive Disease: Hepatitis B virus-associated hepatocellular carcinoma [ICD-11: 2C12.7]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HBV infection in HCC cell lines enhances sorafenib resistance. HBV infection in HCC reduces miR-193b expression and increases Mcl-1 expression. miR-193b directly suppresses the expression of Mcl-1 through its 3'-UTRs. miR-193b facilitates sorafenib-induced apoptosis. miR-193b sensitizes HBV-associated HCC cell lines to sorafenib.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [112]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HL-7702 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [113]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ADAM10 (a distintegrin and metalloprotease family), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and Sk-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice.

Key Molecule: Serum response factor (SRF) [113]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Sorafenib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Tumorigenic properties; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ADAM10 (a distintegrin and metalloprotease family), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and Sk-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice.

Vinblastine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-335 [88]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vinblastine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR335/SIAH2/HDAC3 signaling pathway; Regulation; hsa05206
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue exclusion assay; Transwell assay
• Mechanism Description: miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: E3 ubiquitin-protein ligase SIAH2 (SIAH2) [88]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vinblastine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR335/SIAH2/HDAC3 signaling pathway; Regulation; hsa05206
• In Vitro Model: SNU387 cells; Liver; Homo sapiens (Human); CVCL_0250
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay; Transwell assay
• Mechanism Description: miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-146a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [6]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-122 [55]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-122 could modulate the sensitivity of the HCC cells to chemotherapeutic drugs through downregulating MDR related genes MDR-1, GST-Pi, and MRP, antiapoptotic gene Bcl-w and cell cycle related gene cyclin B1.

Vinpocetine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [114]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Function; Activation
• Sensitive Drug: Vinpocetine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/GSK-3beta signaling pathway; Activation; hsa04931
• In Vitro Model: Saccharomyces cerevisiae strain; 4932
• In Vitro Model: Bacteroides thetaiotaomicron strain; 818
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Sulforhodamine blue (SRB) assay
• Mechanism Description: Enhanced anticancer activity by the combination of vinpocetine and sorafenib via PI3K/AKT/GSK-3beta signaling axis in hepatocellular carcinoma cells. Our study revealed that vinpocetine plus sorafenib could suppress the cytoprotective autophagy induced by vinpocetine and subsequently show synergistically anti-HCC activity via activating GSK-3beta and the combination of vinpocetine and sorafenib might reverse sorafenib resistance via the PI3K/protein kinase B/GSK-3beta signaling axis.

Curcumin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200a [116]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Curcumin
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HepJ5 cells; Liver; Homo sapiens (Human); CVCL_RW48
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression ofmiR-200a/b in HepJ5 cells conferred enhanced resistance tocurcumin treatment compared with the control cells.

Key Molecule: hsa-mir-200b [116]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Curcumin
• 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: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HepJ5 cells; Liver; Homo sapiens (Human); CVCL_RW48
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression ofmiR-200a/b in HepJ5 cells conferred enhanced resistance tocurcumin treatment compared with the control cells.

Patented Agent(s) 1 drug(s) in total

Erastin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: GABPB1 antisense RNA 1 (GABPB1-AS1) [115]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Erastin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells.

Clinical Trial Drug(s) 3 drug(s) in total

Camptothecin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [35]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Very low density lipoprotein receptor (VLDLR) [35]

• Resistant Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: PLC/PRF-5 cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.

TRAIL

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-942 [117]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: TRAIL
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HLCZ01 cells; Hepatoma; Homo sapiens (Human); CVCL_1J92
• In Vitro Model: LH86 cells; Hepatoma; Homo sapiens (Human); CVCL_8889
• In Vitro Model: HLCZ02 cells; Liver; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-942 is upregulated in TRAIL-resistant cancer cells and decreased in TRAIL-sensitive ones. miR-942 is inversely correlated with ISG12a expression in cancer tissues and cells. AkT control TRAIL resistance of cancer cells through downregulation of ISG12a by miR-942. Down-regulation of ISG12a by miR-942 is needed to maintain the TRAIL-resistant phenotype.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interferon alpha-inducible protein 27 (IFI27) [117]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: TRAIL
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HLCZ01 cells; Hepatoma; Homo sapiens (Human); CVCL_1J92
• In Vitro Model: LH86 cells; Hepatoma; Homo sapiens (Human); CVCL_8889
• In Vitro Model: HLCZ02 cells; Liver; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-942 is upregulated in TRAIL-resistant cancer cells and decreased in TRAIL-sensitive ones. miR-942 is inversely correlated with ISG12a expression in cancer tissues and cells. AkT control TRAIL resistance of cancer cells through downregulation of ISG12a by miR-942. Down-regulation of ISG12a by miR-942 is needed to maintain the TRAIL-resistant phenotype.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-138 [118]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: TRAIL
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: HLCZ01 cells; Hepatoma; Homo sapiens (Human); CVCL_1J92
• In Vitro Model: LH86 cells; Hepatoma; Homo sapiens (Human); CVCL_8889
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-138 enhances TRAIL-induced apoptosis through interferon-stimulated gene 15 downregulation in hepatocellular carcinoma cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin-like protein ISG15 (ISG15) [118]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: TRAIL
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: HLCZ01 cells; Hepatoma; Homo sapiens (Human); CVCL_1J92
• In Vitro Model: LH86 cells; Hepatoma; Homo sapiens (Human); CVCL_8889
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-138 enhances TRAIL-induced apoptosis through interferon-stimulated gene 15 downregulation in hepatocellular carcinoma cells.

Betulinic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [119]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Betulinic acid
• 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/p66shc/miR21-Sod2 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Promega
• Mechanism Description: p53 is responsible for the anti-tumor effect of betulinic acid through up-regulation of p66(shc) and miR-21 and down-regulation of Sod2 expression, leading to mitochondrial ROS accumulation and apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Superoxide dismutase Mn (SODM) [119]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Betulinic acid
• 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/p66shc/miR21-Sod2 signaling pathway; Regulation; hsa05206
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Promega
• Mechanism Description: p53 is responsible for the anti-tumor effect of betulinic acid through up-regulation of p66(shc) and miR-21 and down-regulation of Sod2 expression, leading to mitochondrial ROS accumulation and apoptosis.

Preclinical Drug(s) 2 drug(s) in total

CP-31398

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cellular tumor antigen p53 (TP53) [120]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Missense mutation; p.Y220C (c.659A>G)
• Sensitive Drug: CP-31398
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR

Key Molecule: Cellular tumor antigen p53 (TP53) [120]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Missense mutation; p.R249S (c.747G>C)
• Sensitive Drug: CP-31398
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR

Piperlongumine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA 1391 (LINC01391) [121]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Piperlongumine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC-7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vivo Model: Nude mice model; Mus musculus
• Experiment for Molecule Alteration: Microarray assay; qRT-PCR; RNA pull down assay; RIP experiments assay; Knockdown assay; Overexpression assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Piplartine suppresses proliferation and invasion of hepatocellular carcinoma by LINC01391-modulated Wnt/beta-catenin pathway inactivation through ICAT.

Investigative Drug(s) 6 drug(s) in total

5-FU-CDDP

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Maternally expressed 3 (MEG3) [2]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: 5-FU-CDDP
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCC Huh7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: 7721 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: 7402 cells; Uterus; Homo sapiens (Human); CVCL_5492
• In Vitro Model: LO2 cells; Uterus; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Overexpression assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MEG3 overexpression inhibited the proliferation of HCC cells, at least in part by affecting miR-664mediated regulation of ADH4.

Aspirin CD3

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: LMCD1 antisense RNA 1 (LMCD1-AS1) [122]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Aspirin CD3
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Male BALB/c-nu/nu athymic nude mice model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western bloting analysis; Luciferase assay; Immunofluorescence assay; ChIP assay; Immunohistochemistry analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Aspirin targets P4HA2 through inhibiting NF-kappa-B and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma.

Cisplatinum

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 2 (CASC2) [123]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Cisplatinum
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: SMMC-7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Overexpression assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC2 Improves Cisplatin Sensitivity in Hepatocellular Carcinoma Through Sponging miR-222.

Dovitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.M538I
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.M536I
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.L618M
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.I548V
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.M538I
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.M536I
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.L618M
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [60]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.I548V
• Resistant Drug: Dovitinib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Within the FGFR2 gene, mutations such as M536I, M538I, I548V and L618M have been shown through in vitro experiments to confer resistance to drugs like dovitinib.

MET inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [124]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Copy number gain; .
• Sensitive Drug: MET inhibitors
• Experimental Note: Identified from the Human Clinical Data

TAS-120

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V565F
• Resistant Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V565F
• Resistant Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Sensitive Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V565I
• Sensitive Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Sensitive Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.N550H
• Sensitive Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Sensitive Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.E566A
• Sensitive Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Sensitive Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.V565I
• Sensitive Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Sensitive Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.N550H
• Sensitive Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

Key Molecule: Fibroblast growth factor receptor 2 (FGFR2) [125]

• Sensitive Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Molecule Alteration: Missense mutation; p.E566A
• Sensitive Drug: TAS-120
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ctDNA analysis
• Mechanism Description: TAS-120 overcomes resistance to atp-competitive fgfr inhibitors in patients with fgfr2 fusion-positive intrahepatic cholangiocarcinoma.

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