Disease Information

General Information of the Disease (ID: DIS00075)

Name	Liver cancer
ICD	ICD-11: 2C12
Resistance Map

Type(s) of Resistant Mechanism of This Disease

ADTT: Aberration of the Drug's Therapeutic Target

DISM: Drug Inactivation by Structure Modification

EADR: Epigenetic Alteration of DNA, RNA or Protein

IDUE: Irregularity in Drug Uptake and Drug Efflux

MRAP: Metabolic Reprogramming via Altered Pathways

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s)

18 drug(s) in total

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Doxorubicin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Drug Inactivation by Structure Modification (DISM)			Click to Show/Hide
Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4)				[1]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.13E-47 Fold-change: -1.49E+00 Z-score: -1.82E+01
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: Cytochrome P450 family 3 subfamily A member1 (CYP3A4)				[57]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.02E-14 Fold-change: -3.23E-01 Z-score: -1.01E+01
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).
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell 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	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: Multidrug resistance protein 1 (ABCB1)				[6]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
	HCC3 cells	Liver	Homo sapiens (Human)	CVCL_0C57
	LM-6 cells	Liver	Homo sapiens (Human)	CVCL_7680
Experiment for Molecule Alteration	Western blot 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)				[8]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	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)				[21]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
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)				[1]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.54E-01 Fold-change: -1.17E-02 Z-score: -5.93E-01
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)				[57]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.68E-02 Fold-change: -3.05E-02 Z-score: -2.04E+00
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.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2)				[1]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.85E-09 Fold-change: -2.21E-01 Z-score: -6.58E+00
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.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Solute carrier family 16 member 1 (SLC16A1)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.16E-02 Fold-change: -8.65E-02 Z-score: -1.75E+00
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 blot 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)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.55E-07 Fold-change: -3.93E-01 Z-score: -5.40E+00
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 blot 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: Extracellular matrix receptor III (CD44)				[4]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.11E-07 Fold-change: -3.65E-01 Z-score: -5.35E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	PLC/PRF/5 cells	Liver	Homo sapiens (Human)	CVCL_0485
	HLE cells	Liver	Homo sapiens (Human)	CVCL_1281
	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: Eukaryotic translation initiation factor 5A-2 (EIF5A2)				[14]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.55E-07 Fold-change: -1.37E-01 Z-score: -5.30E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SNU449 cells	Liver	Homo sapiens (Human)	CVCL_0454
	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: E3 ubiquitin-protein ligase Mdm2 (MDM2)				[28]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.50E-04 Fold-change: 7.14E-02 Z-score: 4.02E+00
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
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-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: Serine/threonine-protein kinase ULK1 (ULK1)				[51]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.08E-01 Fold-change: -9.36E-03 Z-score: -6.67E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell autophagy		Inhibition	hsa04140
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Neurogenic locus notch homolog protein 1 (NOTCH1)				[64]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.89E-08 Fold-change: -6.17E-02 Z-score: -6.03E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell colony		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
	Notch1/HES1-PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit (SDHB)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.20E-07 Fold-change: -7.20E-02 Z-score: -6.01E+00
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 blot 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: Nuclear receptor subfamily 1 group I3 (NR1I3)				[70]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 7.11E-12 Fold-change: -2.10E-01 Z-score: -7.96E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: WT1 antisense RNA (WT1-AS)				[45]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.13E-02 Fold-change: 1.93E+00 Z-score: 2.56E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	JAKT2/STAT3/MAPK signaling pathway		Inhibition	hsa04659
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: WT1 antisense RNA (WT1-AS)				[45]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.36E-02 Fold-change: -7.29E-02 Z-score: -2.56E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	JAKT2/STAT3/MAPK signaling pathway		Inhibition	hsa04659
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Metalloproteinase inhibitor 3 (TIMP3)				[3]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.51E-20 Fold-change: -6.09E-01 Z-score: -9.89E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	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 blot 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: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11)				[18]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.92E-03 Fold-change: -6.39E-02 Z-score: -2.73E+00
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	QGY-7703 cells	Liver	Homo sapiens (Human)	CVCL_6715
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	97H cells	Liver	Homo sapiens (Human)	N.A.
	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: High mobility group protein HMGI-C (HMGA2)				[23]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.13E-05 Fold-change: 1.02E+00 Z-score: 4.33E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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)				[18]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 7.82E-08 Fold-change: -4.84E-02 Z-score: -6.18E+00
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	QGY-7703 cells	Liver	Homo sapiens (Human)	CVCL_6715
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	97H cells	Liver	Homo sapiens (Human)	N.A.
	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)				[18]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.66E-06 Fold-change: -3.66E-01 Z-score: -5.01E+00
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	QGY-7703 cells	Liver	Homo sapiens (Human)	CVCL_6715
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	97H cells	Liver	Homo sapiens (Human)	N.A.
	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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR)				[37]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.01E-01 Fold-change: 3.08E-01 Z-score: 6.79E-01
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
	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: H19, imprinted maternally expressed transcript (H19)				[40]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.95E-05 Fold-change: 2.36E+00 Z-score: 4.33E+00
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.
Key Molecule: Ribosomal protein L13a pseudogene 20 (RPL13AP20)				[46]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.79E-22 Fold-change: 1.61E+00 Z-score: 1.02E+01
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	GSKIP/GSK-3beta signaling pathway		Activation	hsa04550
	Tumorigenesis		Activation	hsa05206
	Wnt/Beta-catenin signaling pathway		Activation	hsa04310
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	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.

Methotrexate

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Solute carrier family 16 member 1 (SLC16A1)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Methotrexate			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.16E-02 Fold-change: -8.65E-02 Z-score: -1.75E+00
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 blot 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)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Methotrexate			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.55E-07 Fold-change: -3.93E-01 Z-score: -5.40E+00
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 blot 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: Glyceraldehyde-3-phosphate dehydrogenase 1 (GAPDH)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Methotrexate			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.06E-16 Fold-change: -2.37E-01 Z-score: -9.03E+00
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 blot 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)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Methotrexate			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.12E-01 Fold-change: -2.17E-03 Z-score: -2.39E-01
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 blot 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)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Methotrexate			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.42E-01 Fold-change: -9.83E-03 Z-score: -4.67E-01
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 blot 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)				[2]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Methotrexate			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.45E-02 Fold-change: -2.85E-02 Z-score: -2.04E+00
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 blot 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.

Cisplatin

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Runt-related transcription factor 3 (RUNX3)				[5]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.06E-03 Fold-change: -2.47E-01 Z-score: -2.99E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	Wnt/Beta-catenin signaling pathway		Activation	hsa04310
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HEK293 cells	Kidney	Homo sapiens (Human)	CVCL_0045
Experiment for Molecule Alteration	Western blot 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: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[9]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.38E-03 Fold-change: 1.01E-01 Z-score: 3.23E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	miR363/Mcl-1 signaling pathway		Regulation	N.A.
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: High mobility group protein HMGI-C (HMGA2)				[23]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.13E-05 Fold-change: 1.02E+00 Z-score: 4.33E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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: Y-box-binding protein 1 (YBX1)				[26]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.97E-03 Fold-change: 7.34E-02 Z-score: 3.27E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	Tumorigenesis		Activation	hsa05206
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)				[29]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.50E-08 Fold-change: 5.98E-02 Z-score: 6.40E+00
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-199a-5p levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. Downregulated miR-199a-5p enhanced autophagy activation by targeting ATG7. Cisplatin-induced downregulation of miR-199a-5p increases cell proliferation by activating autophagy.
Key Molecule: Transcription factor SOX-9 (SOX9)				[22]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.48E-30 Fold-change: 5.00E-01 Z-score: 1.53E+01
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	SOX9 signaling pathway		Activation	hsa04024
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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: Tumor protein p53-inducible nuclear protein 1 (TP53INP1)				[67]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.59E-05 Fold-change: -9.30E-02 Z-score: -4.59E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	miR182/TP53INP1 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HEK293 cells	Kidney	Homo sapiens (Human)	CVCL_0045
Experiment for Molecule Alteration	Western blot 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: Signal transducer activator transcription 3 (STAT3)				[19], [39]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Phosphorylation		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell cycle		Activation	hsa04110
	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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Novel transcript, overlapping ACER2 (RP11-363E7.4)				[24]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.43E-02 Fold-change: 8.37E-01 Z-score: 2.56E+00
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: Colorectal neoplasia differentially expressed (CRNDE)				[23]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.38E-37 Fold-change: 3.03E+00 Z-score: 1.42E+01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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: HOX transcript antisense RNA (HOTAIR)				[19], [39]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.32E-02 Fold-change: 2.60E+00 Z-score: 2.56E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell growth		Activation	hsa05200
	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				[23]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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				[22]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	SOX9 signaling pathway		Activation	hsa04024
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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)				[24]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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 )				[24]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
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)				[26]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell cytotoxicity		Inhibition	hsa04650
	Tumorigenesis		Activation	hsa05206
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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)				[80]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	NRAL/miR340-5p/Nrf2 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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				[80]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	NRAL/miR340-5p/Nrf2 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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				[9]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	miR363/Mcl-1 signaling pathway		Regulation	N.A.
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				[67]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	miR182/TP53INP1 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[5]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell adhesion		Inhibition	hsa04514
	Cell apoptosis		Inhibition	hsa04210
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Wnt/Beta-catenin signaling pathway		Activation	hsa04310
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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				[29]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
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
	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)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[19]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
	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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[16]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	mTOR signaling pathway		Inhibition	hsa04150
In Vitro Model	GBC-SD cells	Gallbladder	Homo sapiens (Human)	CVCL_6903
	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)			Click to Show/Hide
Key Molecule: Signal transducer activator transcription 3 (STAT3)				[19]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.12E-04 Fold-change: -1.39E-01 Z-score: -3.93E+00
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: Bcl-2-associated agonist of cell death (BAD)				[11]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.27E-01 Fold-change: -1.47E-02 Z-score: -8.01E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	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: NFE2-related factor 2 (NRF2)				[54]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.05E-01 Fold-change: -1.68E-02 Z-score: -5.21E-01
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
	KkU-M156 cells	Gallbladder	Homo sapiens (Human)	CVCL_M260
	KkU-M213 cells	Gallbladder	Homo sapiens (Human)	CVCL_M261
	KkU-M214 cells	Gallbladder	Homo sapiens (Human)	CVCL_M264
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Acri-dine orange and ethidium bromide (AO/EB) fluorescent dyes assay
Mechanism Description	Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant, cytoprotective, and metabolic enzymes, plays important roles in drug resistance and proliferation in cancer cells. Nrf2 mRNA expression of kkU-M156 and kkU-100 cells, representatives of low and high-Nrf2-expressing CCA cells, were silenced using siRNA. After knockdown of Nrf2, the sensitivity of those cells to the cytotoxicity of cisplatin (Cis) was enhanced in association with the increased release of AIF and downregulation of Bcl-xl in both cells.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[81]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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)				[16]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
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
	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)				[82]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	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: Cyclin-G1 (CCNG1)				[83]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	miR27b/CCNG1/p53 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SNU182 cells	Liver	Homo sapiens (Human)	CVCL_0090
	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)			Click to Show/Hide
Key Molecule: TPTE pseudogene 1 (TPTEP1)				[38]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.28E-01 Fold-change: 2.78E-02 Z-score: 9.02E-02
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	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)				[19]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
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				[81]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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				[16]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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
	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				[82]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	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				[11]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	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				[11]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	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				[83]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	miR27b/CCNG1/p53 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SNU182 cells	Liver	Homo sapiens (Human)	CVCL_0090
	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				[84]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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)				[85]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
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 blot 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				[85]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[85]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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.

Paclitaxel

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[6]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Paclitaxel			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
	HCC3 cells	Liver	Homo sapiens (Human)	CVCL_0C57
	LM-6 cells	Liver	Homo sapiens (Human)	CVCL_7680
Experiment for Molecule Alteration	Western blot 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.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: I-kappa-B-kinase beta (IKKB)				[31]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Paclitaxel			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.19E-03 Fold-change: 4.24E-02 Z-score: 3.17E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
	NF-kappaB signaling pathway		Activation	hsa04064
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	BEL-7404 cells	Liver	Homo sapiens (Human)	CVCL_6568
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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.

Fluorouracil

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Bcl-2-associated agonist of cell death (BAD)				[10], [11]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.19E-09 Fold-change: -2.62E-01 Z-score: -6.15E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	Mitochondrial signaling pathway		Activation	hsa04217
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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: Kelch-like ECH-associated protein 1 (KEAP1)				[33]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.51E-03 Fold-change: 3.81E-02 Z-score: 3.34E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	Nrf2 signaling pathway		Inhibition	hsa05208
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: High mobility group protein HMGI-C (HMGA2)				[56]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.56E-02 Fold-change: -2.08E-02 Z-score: -2.15E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell colony		Activation	hsa05200
	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: Bcl-2-like protein 2 (BCL2L2)				[58]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.79E-03 Fold-change: -3.17E-02 Z-score: -2.69E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	Bel-7402/5-Fu cells	Liver	Homo sapiens (Human)	CVCL_5493
Experiment for Molecule Alteration	Western blot 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.
Key Molecule: Suppressor of cytokine signaling 6 (SOCS6)				[66]
Sensitive Disease	Hepatocellular cancer [ICD-11: 2C12.4]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.24E-04 Fold-change: -7.85E-02 Z-score: -3.85E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
	miR183/IDH2/SOCS6/HIF1alpha feedback loop signaling pathway		Regulation	N.A.
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.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1)				[43]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.43E-07 Fold-change: 2.16E+00 Z-score: 6.36E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell colony		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22)				[15]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.48E-08 Fold-change: 3.19E-01 Z-score: 5.81E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	PLC cells	Liver	Homo sapiens (Human)	CVCL_0485
	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: High mobility group protein HMGI-C (HMGA2)				[23]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.13E-05 Fold-change: 1.02E+00 Z-score: 4.33E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	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: Nuclear receptor subfamily 2 group C2 (NR2C2)				[27]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.03E-05 Fold-change: 7.29E-02 Z-score: 4.71E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
	MHCC97-H cells	Liver	Homo sapiens (Human)	CVCL_4972
	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: Eukaryotic translation initiation factor 4E (EIF4E)				[55]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.85E-01 Fold-change: -1.87E-02 Z-score: -8.76E-01
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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: Dual specificity protein phosphatase 6 (DUSP6)				[59]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.96E-02 Fold-change: -3.20E-02 Z-score: -1.92E+00
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: Phosphatase and tensin homolog (PTEN)				[61]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.86E-04 Fold-change: -4.60E-02 Z-score: -3.95E+00
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	PLC/PRF/5 cells	Liver	Homo sapiens (Human)	CVCL_0485
	HLE cells	Liver	Homo sapiens (Human)	CVCL_1281
	HLF cells	Liver	Homo sapiens (Human)	CVCL_2947
Experiment for Molecule Alteration	Western blot 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.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Small nucleolar RNA host gene 6 (SNHG6)				[27]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.03E-20 Fold-change: 1.59E+00 Z-score: 9.61E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
	MHCC97-H cells	Liver	Homo sapiens (Human)	CVCL_4972
	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.

Oxaliplatin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[12]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Oxaliplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	Wnt/Beta-catenin signaling pathway		Inhibition	hsa04310
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-122 inhibits MDR1 expression via suppression of Wnt/beta-catenin pathway, thereby enhancing HCC sensitivity to OXA.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22)				[15]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Oxaliplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.48E-08 Fold-change: 3.19E-01 Z-score: 5.81E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	PLC cells	Liver	Homo sapiens (Human)	CVCL_0485
	L02 cells	Liver	Homo sapiens (Human)	CVCL_6926
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1)				[41]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Oxaliplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.01E-06 Fold-change: 2.31E+00 Z-score: 5.87E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Cell viability		Activation	hsa05200
	miR7-5p/ABCC1 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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)				[47]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Oxaliplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.95E-01 Fold-change: 1.56E-01 Z-score: 1.30E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
	Epithelial mesenchymal transition signaling pathway		Activation	hsa01521
	NR2F1/AS1/miR363/ABCC1 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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)			Click to Show/Hide
Key Molecule: Multidrug resistance-associated protein 1 (MRP1)				[41]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Oxaliplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.12E-23 Fold-change: 1.52E-01 Z-score: 1.09E+01
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	miR7-5p/ABCC1 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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.

Sorafenib

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Serpin B3 (SERPINB3)				[13]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.77E-02 Fold-change: -1.25E-01 Z-score: -1.99E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Platelet-derived growth factor receptor beta (PDGFRB)				[20]
Sensitive Disease	Liver cancer [ICD-11: 2C12.6]
Sensitive Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.23E-04 Fold-change: -1.35E-01 Z-score: -3.35E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	MAPK signaling pathway		Inhibition	hsa04010
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Ras association domain-containing protein 1 (RASSF1)				[32]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.26E-03 Fold-change: 3.99E-02 Z-score: 3.40E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	MAPK signaling pathway		Inhibition	hsa04010
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Serum response factor (SRF)				[52]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.01E-01 Fold-change: -1.02E-02 Z-score: -1.04E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Angiogenic potential		Inhibition	hsa04370
	Cell apoptosis		Activation	hsa04210
	Tumorigenic properties		Inhibition	hsa05200
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot 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: Apoptosis regulator Bcl-2 (BCL2)				[62]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.81E-06 Fold-change: -5.23E-02 Z-score: -5.27E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HL-7702 cells	Liver	Homo sapiens (Human)	CVCL_6926
	MHCC97-H cells	Liver	Homo sapiens (Human)	CVCL_4972
Experiment for Molecule Alteration	Western blot 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: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[69]
Sensitive Disease	Hepatitis B virus-associated hepatocellular carcinoma [ICD-11: 2C12.7]
Sensitive Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.17E-05 Fold-change: -1.54E-01 Z-score: -4.39E+00
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
	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.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Transcription factor SOX-9 (SOX9)				[22]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.00E-11 Fold-change: 5.72E-01 Z-score: 6.96E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	SOX9 signaling pathway		Activation	hsa04024
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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: Hepatocyte growth factor receptor (MET)				[25]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.24E-01 Fold-change: 3.24E-03 Z-score: 9.61E-02
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	c-Met/AKT signaling pathway		Inhibition	hsa01521
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Pyruvate kinase M2 (PKM)				[44]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.02E-21 Fold-change: 1.99E-01 Z-score: 1.08E+01
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
	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: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1)				[44]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.41E-05 Fold-change: 1.29E-01 Z-score: 4.81E+00
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
	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: Cyclin-dependent kinase inhibitor 1B (CDKN1B)				[50]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.77E-01 Fold-change: -8.15E-03 Z-score: -8.88E-01
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	PLC/PRF/5 cells	Liver	Homo sapiens (Human)	CVCL_0485
	SNU182 cells	Liver	Homo sapiens (Human)	CVCL_0090
	SNU398 cells	Liver	Homo sapiens (Human)	CVCL_0077
	SNU449 cells	Liver	Homo sapiens (Human)	CVCL_0454
	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: RasGAP-activating-like protein 1 (RASAL1)				[53]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.18E-01 Fold-change: -1.60E-02 Z-score: -1.59E+00
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
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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: Mothers against decapentaplegic homolog 7 (SMAD7)				[65]
Resistant Disease	Liver cancer [ICD-11: 2C12.6]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.57E-03 Fold-change: -7.38E-02 Z-score: -3.30E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	PI3K/AKT signaling pathway		Activation	hsa04151
	TGF-beta signaling pathway		Activation	hsa04350
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	BEL-7404 cells	Liver	Homo sapiens (Human)	CVCL_6568
	PLC/PRF/5 cells	Liver	Homo sapiens (Human)	CVCL_0485
	SNU449 cells	Liver	Homo sapiens (Human)	CVCL_0454
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
	HLE cells	Liver	Homo sapiens (Human)	CVCL_1281
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot 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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1)				[25]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 7.40E-03 Fold-change: 8.19E-01 Z-score: 2.97E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	c-Met/AKT signaling pathway		Inhibition	hsa01521
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Homeobox protein Hox-A13 (HOXA13)				[34]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 7.39E-37 Fold-change: 3.53E-01 Z-score: 1.40E+01
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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: Small nucleolar RNA host gene 1 (SNHG1)				[36]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.23E-12 Fold-change: 3.22E+00 Z-score: 1.06E+01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT signaling pathway		Activation	hsa04151
	Cell apoptosis		Inhibition	hsa04210
	Cell autophagy		Inhibition	hsa04140
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Very low density lipoprotein receptor (VLDLR)				[35]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.58E-05 Fold-change: 3.24E+00 Z-score: 5.00E+00
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
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	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.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Lymphocyte activation antigen 4F2 (SLC3A2)				[36]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Sorafenib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.35E-01 Fold-change: 1.01E-02 Z-score: 7.85E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT signaling pathway		Activation	hsa04151
	Cell apoptosis		Inhibition	hsa04210
	Cell autophagy		Inhibition	hsa04140
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	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.

IFN-alpha

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Cellular tumor antigen p53 (TP53)				[30]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	IFN-alpha			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.64E-02 Fold-change: 5.45E-02 Z-score: 2.27E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	NF-kappaB p65/p53 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	PLC cells	Liver	Homo sapiens (Human)	CVCL_0485
	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.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Long non-protein coding RNA 607 (LINC00607)				[30]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	IFN-alpha			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.77E-09 Fold-change: 1.72E+00 Z-score: 5.94E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	NF-kappaB p65/p53 signaling pathway		Regulation	N.A.
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	PLC cells	Liver	Homo sapiens (Human)	CVCL_0485
	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.

Gemcitabine

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Tyrosine-protein phosphatase non-receptor type 12 (PTPN12)				[42]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Gemcitabine			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.74E-06 Fold-change: 2.24E-01 Z-score: 5.27E+00
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
	KMCH-1 cells	Gallbladder	Homo sapiens (Human)	CVCL_7970
	Mz-ChA-1 cells	Gallbladder	Homo sapiens (Human)	CVCL_6932
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot 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: PI3-kinase regulatory subunit alpha (PIK3R1)				[63]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Gemcitabine			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.13E-05 Fold-change: -7.38E-02 Z-score: -4.75E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HuCCT1 cells	Bile duct	Homo sapiens (Human)	CVCL_0324
	HuH28 cells	Bile duct	Homo sapiens (Human)	CVCL_2955
Experiment for Molecule Alteration	Western blot 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.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Collagenase 72 kDa type IV collagenase (MMP2)				[63]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Gemcitabine			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.80E-06 Fold-change: -5.35E-02 Z-score: -5.09E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HuCCT1 cells	Bile duct	Homo sapiens (Human)	CVCL_0324
	HuH28 cells	Bile duct	Homo sapiens (Human)	CVCL_2955
Experiment for Molecule Alteration	Western blot 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.

Pirarubicin

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22)				[15]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Pirarubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.03E-01 Fold-change: 1.99E-03 Z-score: 2.50E-01
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	PLC cells	Liver	Homo sapiens (Human)	CVCL_0485
	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.

Baicalein

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: NF-kappaB interacting LncRNA (NKILA)				[48]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Baicalein			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.64E-05 Fold-change: 1.31E+00 Z-score: 4.03E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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)			Click to Show/Hide
Key Molecule: NF-kappa-B inhibitor alpha (NFKBIA)				[48]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Baicalein			Drug Info
Molecule Alteration	Phosphorylation		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
	NF-kappaB signaling pathway		Inhibition	hsa04064
In Vitro Model	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	HCCLM3 cells	Liver	Homo sapiens (Human)	CVCL_6832
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	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.

Etoposide

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)				[49]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Etoposide			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.39E-14 Fold-change: 1.27E-01 Z-score: 8.66E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	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.

Cetuximab

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Signal transducer activator transcription 3 (STAT3)				[60]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.50E-03 Fold-change: -4.36E-02 Z-score: -2.83E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SNU449 cells	Liver	Homo sapiens (Human)	CVCL_0454
	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.
Key Molecule: Oncogenic epidermal growth factor receptor (EGFR)				[79]
Sensitive Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Discovered Using In-vivo Testing Model
Cell Pathway Regulation	EGF-EGFR signaling pathway		Regulation	N.A.
In Vivo Model	Mouse model			Mus musculus
Experiment for Molecule Alteration	Immunoprecipitation assay; LC-MS/MS analysis
Experiment for Drug Resistance	Cellular ROS and lipid peroxidation level assay; LOXL3 enzymatic assay; In vitro kinase assay
Mechanism Description	To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-let-7a				[60]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SNU449 cells	Liver	Homo sapiens (Human)	CVCL_0454
	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.

Acetaminophen

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Long non-protein coding RNA (HNF4A-AS1)				[74]
Resistant Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Resistant Drug	Acetaminophen			Drug Info
Molecule Alteration	.		Expression	Molecule Info
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)				[74]
Resistant Disease	Cholangiocarcinoma [ICD-11: 2C12.0]
Resistant Drug	Acetaminophen			Drug Info
Molecule Alteration	.		Expression	Molecule Info
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

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Maternally expressed 3 (MEG3)				[75]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Adenosine			Drug Info
Molecule Alteration	Up-regulation		Interaction	Molecule Info
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
	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

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-539				[76]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	Arsenic trioxide			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	PLC/PRF/5 cells	Liver	Homo sapiens (Human)	CVCL_0485
	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.

Bortezomib

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-101				[77]
Sensitive Disease	Hepatocellular cancer [ICD-11: 2C12.4]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	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)			Click to Show/Hide
Key Molecule: Proteasome maturation protein (POMP)				[77]
Sensitive Disease	Hepatocellular cancer [ICD-11: 2C12.4]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	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

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-146a				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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				[78]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Carboplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
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.

Clinical Trial Drug(s)

2 drug(s) in total

Click to Show/Hide the Full List of Drugs

TRAIL

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Interferon alpha-inducible protein 27 (IFI27)				[7]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	TRAIL			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.37E-02 Fold-change: -1.60E-01 Z-score: -1.68E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HLCZ01 cells	Hepatoma	Homo sapiens (Human)	CVCL_1J92
	LH86 cells	Hepatoma	Homo sapiens (Human)	CVCL_8889
	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
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ubiquitin-like protein ISG15 (ISG15)				[17]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Sensitive Drug	TRAIL			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.21E-01 Fold-change: -7.00E-03 Z-score: -9.97E-02
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
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	HLCZ01 cells	Hepatoma	Homo sapiens (Human)	CVCL_1J92
	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

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Superoxide dismutase Mn (SODM)				[68]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]
Resistant Drug	Betulinic acid			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 7.96E-07 Fold-change: -1.28E-01 Z-score: -5.52E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	p53/p66shc/miR21-Sod2 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	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.

References

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Ref 31	Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-kB signaling pathway in hepatocellular carcinoma. Biochem Biophys Res Commun. 2018 Sep 5;503(2):1035-1041. doi: 10.1016/j.bbrc.2018.06.113. Epub 2018 Aug 2.
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Prof. Feng ZHU (zhufeng@zju.edu.cn)