Drug Information

Drug (ID: DG00282) and It's Reported Resistant Information
Name
Sorafenib
Synonyms
Nexavar; Sorafenibum; Sorafenib [INN]; Nexavar (TN); Sorafenib (INN); N-[4-Chloro-3-(trifluoromethyl)phenyl]-N'-[4-[2-(N-methylcarbamoyl)-4-pyridyloxy]phenyl]urea; N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcar bamoyl)-4-pyridyloxy)phenyl)urea; 4(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N(sup 2)-methylpyridine-2-carboxamide; 4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide; 4-(4-(3-(4-chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxyllic acid methyamide-4-methylbenzenesulfonate; 4-(4-{3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido}phenoxy)-N(sup 2)-methylpyridine-2-carboxamide; 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide; 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE; Sorafenib (Pan-TK inhibitor)
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Indication
In total 3 Indication(s)
Renal cell carcinoma [ICD-11: 2C90]
Approved
[1]
Liver cancer [ICD-11: 2C12]
Phase 3
[1]
Myelodysplastic syndrome [ICD-11: 2A37]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
Acute myeloid leukemia [ICD-11: 2A60]
[2]
Kidney cancer [ICD-11: 2C90]
[3]
Liver cancer [ICD-11: 2C12]
[4]
Nonalcoholic fatty liver disease [ICD-11: DB92]
[5]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Liver cancer [ICD-11: 2C12]
[6]
Target Epidermal growth factor receptor (EGFR) EGFR_HUMAN [1]
Platelet-derived growth factor receptor beta (PDGFRB) PGFRB_HUMAN [1]
Tyrosine-protein kinase Kit (KIT) KIT_HUMAN [1]
Vascular endothelial growth factor receptor 2 (KDR) VGFR2_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C21H16ClF3N4O3
IsoSMILES
CNC(=O)C1=NC=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F
InChI
1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
InChIKey
MLDQJTXFUGDVEO-UHFFFAOYSA-N
PubChem CID
216239
ChEBI ID
CHEBI:50924
TTD Drug ID
D0W5HK
VARIDT ID
DR00304
INTEDE ID
DR1500
DrugBank ID
DB00398
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
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Acute myeloid leukemia [ICD-11: 2A60]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [7]
Molecule Alteration Missense mutation
p.F691
 Molecule Info 
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Southern blot analysis; Spectral karyotyping assay
Mechanism Description FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [7]
Molecule Alteration Missense mutation
p.D835
 Molecule Info 
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Southern blot analysis; Spectral karyotyping assay
Mechanism Description FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]
Molecule Alteration Missense mutation
p.D835Y
 Molecule Info 
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 Aldefluor activity analysis
Mechanism Description Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2], [8]
Molecule Alteration Missense mutation
p.D835H
 Molecule Info 
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 Aldefluor activity analysis
Mechanism Description Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [8]
Molecule Alteration Missense mutation
p.F691L
 Molecule Info 
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep amplicon sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.
Liver cancer [ICD-11: 2C12]
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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-374b [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR-374b/hnRNPA1/PkM2 axis functions as an important mechanism in sorafenib resistance, with sorafenib-induced miR-374b downregulation and subsequently elevated glycolysis.
Key Molecule: hsa-miR-613 [9]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Liver cancer [ICD-11: 2C12.6]
 Disease 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: Small nucleolar RNA host gene 1 (SNHG1) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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.
Key Molecule: hsa-mir-21 [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.
Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [11]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: hsa-mir-335 [11]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 qRT-PCR; Dual-luciferase reporter assay
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description LncRNA NEAT1 mediates Sora resistance of HCC cells by suppressing miR-335 expression, and disinhibition on c-Met-Akt signaling pathway.
Key Molecule: hsa-mir-494 [12]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 qPCR; RT-sqPCR
Experiment for
Drug Resistance		 Cell viability assay; Caspase-3/7 activity assay; WB analysis
Mechanism Description miR494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines, by targeting p27, pten, and puma.
Key Molecule: Homeobox protein Hox-A13 (HOXA13) [13]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: hsa-mir-221 [14]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
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
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Caspase 3/7 activity assay; Cell-titer-Glo assay; Flow cytometry assay
Mechanism Description In hepatocellular carcinoma miR221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis.
Key Molecule: PCBP2 overlapping transcript 1 (PCBP2-OT1) [15]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Long non-coding RNA TUC338 is functionally involved in sorafenib-sensitized hepatocarcinoma cells by targeting RASAL1. knockdown of TUC338 was accompanied with increased expression of RASAL1 in HCC cell line with increased proliferation and invasion ability, knockdown of TUC338 could activate the RASAL1 pathway and inhibit tumor growth genes by directly targeting RASAL1 3'-UTR.
Key Molecule: hsa-miR-19a-3p [16]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
PTEN/AKT signaling pathway Inhibition hsa05235
In Vitro Model 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
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-19a-3p induces sorafenib resistance through downregulation of PTEN expression.
Key Molecule: hsa-mir-222 [17]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Regulation hsa04151
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
HL-7702 cells Liver Homo sapiens (Human) CVCL_6926
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR 222 facilitate sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma.
Key Molecule: hsa-mir-216a [4]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.
Key Molecule: hsa-mir-217 [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.
Key Molecule: hsa-mir-375 [18]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatic carcinoma [ICD-11: 2C12.3]
 Disease Info 
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
Huh7 cells Kidney Homo sapiens (Human) CVCL_U442
Huh1 cells Liver Homo sapiens (Human) CVCL_2956
In Vivo Model BALB/c athymic nude mice Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR; Western blotting analysis; ELISA assay
Mechanism Description The expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. The expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1).
Key Molecule: hsa-mir-375 [18]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatic carcinoma [ICD-11: 2C12.3]
 Disease Info 
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
Huh7 cells Kidney Homo sapiens (Human) CVCL_U442
Huh1 cells Liver Homo sapiens (Human) CVCL_2956
In Vivo Model BALB/c athymic nude mice Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR; Western blotting analysis; ELISA assay
Mechanism Description The expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. The expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1).
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Lymphocyte activation antigen 4F2 (SLC3A2) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular cancer [ICD-11: 2C12.4]
 Disease Info 
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
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay; Flow cytometry assay
Mechanism Description LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.
Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay; Flow cytometry assay
Mechanism Description LincRNA-VLDLR (linc-VLDLR) was significantly up-regulated in malignant hepatocytes. Exposure of HCC cells to diverse anti-cancer agents such as sorafenib, camptothecin, and doxorubicin increased linc-VLDLR expression in cells as well as within EVs released from these cells. Incubation with EVs reduced chemotherapy-induced cell death and also increased linc-VLDLR expression in recipient cells. RNAi-mediated knockdown of linc-VLDLR decreased cell viability and abrogated cell cycle progression. Moreover, knockdown of VLDLR reduced expression of ABCG2 (ATP-binding cassette, sub-family G member 2), whereas over-expression of this protein reduced the effects of VLDLR knockdown on sorafenib-induced cell death. Here, linc-VLDLR is identified as an extracellular vesicle enriched LncRNA that contributes to cellular stress responses.
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Very low density lipoprotein receptor (VLDLR) [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular cancer [ICD-11: 2C12.4]
 Disease Info 
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.
Key Molecule: Very low density lipoprotein receptor (VLDLR) [6]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Pyruvate kinase M2 (PKM) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Transcription factor SOX-9 (SOX9) [9]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Liver cancer [ICD-11: 2C12.6]
 Disease 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		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description The drug sensitivity of HCC to sorafenib and cisplatin was significantly decreased when miR-613 was knockdown, suggesting that miR-613 played a possible role in the treatment of HCC drug resistance.
Key Molecule: RAC serine/threonine-protein kinase (AKT) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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 LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.
Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [10]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.
Key Molecule: Hepatocyte growth factor receptor (MET) [11]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [12]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Phosphatase and tensin homolog (PTEN) [12]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Bcl-2-binding component 3 (BBC3) [12]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Caspase-3 (CASP3) [14]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
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
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Caspase 3/7 activity assay; Cell-titer-Glo assay; Flow cytometry assay
Mechanism Description In hepatocellular carcinoma miR221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis.
Key Molecule: RasGAP-activating-like protein 1 (RASAL1) [15]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Phosphatase and tensin homolog (PTEN) [16]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
PTEN/AKT signaling pathway Inhibition hsa05235
In Vitro Model 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
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-19a-3p induces sorafenib resistance through downregulation of PTEN expression.
Key Molecule: Phosphatase and tensin homolog (PTEN) [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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 blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.
Key Molecule: Mothers against decapentaplegic homolog 7 (SMAD7) [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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 blotting analysis; Immunofluorescence analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Overexpression of miR-216a/217 activates the PI3k/Akt and TGF-beta pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis, sorafenib resistance and tumor recurrence in HCC.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [19]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
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: hsa-mir-378 [20]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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		 RT-qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description miR 378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRbeta and c Raf. Sorafenib can suppress tumor growth through the inhibition of multiple tyrosine kinases, including VEGFR, PDGFRbeta and c-Raf.
Key Molecule: hsa-mir-137 [21]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
Huh7-R cells Liver Homo sapiens (Human) CVCL_0336
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Wound healing assay; Anoikis assays
Mechanism Description Upregulation of miR137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma.
Key Molecule: hsa-miR-367-3p [22]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
MDM2/AR-FkBP5/PHLPP signaling pathway Regulation hsa04115
AKT/ERK signaling pathway Regulation hsa04010
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
SNU398 cells Liver Homo sapiens (Human) CVCL_0077
Skhep1 cells Liver Homo sapiens (Human) CVCL_0525
HA22T cells Liver Homo sapiens (Human) CVCL_7046
SNU423 cells Liver Homo sapiens (Human) CVCL_0366
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 3D Invasion Assay
Mechanism Description miR367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FkBP5 and PHLPP, thus dephosphorylating and inactivating AkT and ERk, to suppress the HCC cell invasion. miR367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FkBP5/PHLPP/(pAkT and pERk) signals to better suppress HCC metastasis.
Key Molecule: hsa-mir-122 [23]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 RT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-122 overexpression increased sorafenib sensitivity in treated cells via downregulating SerpinB3 expression.
Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [24]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
STAT3 signaling pathway Inhibition hsa04550
In Vitro Model HCCLM3 cells Liver Homo sapiens (Human) CVCL_6832
SMMC7721 cells Uterus Homo sapiens (Human) CVCL_0534
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Interference lncARSR suppressed liver CSCs expansion and the phosphorylation of the STAT3 molecule was evidently inactivated in both the SMMC7721 si-lncARSR and HCCLM3 si-lncARSR cells.
Key Molecule: hsa-mir-181a [25]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Caspase 3/7 activity analysis; CCK8 assay
Mechanism Description miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.
Key Molecule: hsa-mir-122 [26]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
RAS/RAF/ERK signaling pathway Inhibition hsa04010
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
T1115 cells Liver Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay;
Mechanism Description Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance.
Key Molecule: hsa-mir-27b [19]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
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-338-3p [27]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular cancer [ICD-11: 2C12.4]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
HIF signaling signaling pathway Inhibition hsa04066
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
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description Overexpression of miR-338-3p inhibited HIF-1alpha 3'-UTR luciferase activity and HIF-1alpha protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1alpha overexpression rescued and HIF-1alpha knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1alpha. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1alpha.
Key Molecule: hsa-miR-425-3p [28]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 HCC cells Liver Homo sapiens (Human) CVCL_0027
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; EdU assay
Mechanism Description miR-425-3p levels were induced by sorafenib incubation in HuH-7 cells-derived exosomes, and this cell line was more sensitive to cell death after incubation with the drug. The involvement of extracellular vesicles in modulating HCC response to sorafenib has recently emerged providing a potential novel strategy to interfere with HCC chemoresistance.
Key Molecule: hsa-mir-193b [29]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatitis B virus-associated hepatocellular carcinoma [ICD-11: 2C12.7]
 Disease 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
L02 cells Liver Homo sapiens (Human) CVCL_6926
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description HBV infection in HCC cell lines enhances sorafenib resistance. HBV infection in HCC reduces miR-193b expression and increases Mcl-1 expression. miR-193b directly suppresses the expression of Mcl-1 through its 3'-UTRs. miR-193b facilitates sorafenib-induced apoptosis. miR-193b sensitizes HBV-associated HCC cell lines to sorafenib.
Key Molecule: hsa-mir-34 [30]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression.
Key Molecule: hsa-mir-122 [31]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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		 RT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ADAM10 (a distintegrin and metalloprotease family), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and Sk-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1) [20]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
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: Platelet-derived growth factor receptor beta (PDGFRB) [20]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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: Vascular endothelial growth factor (VEGFR) [20]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
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: ADP/ATP translocase 2 (ANT2) [21]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
Huh7-R cells Liver Homo sapiens (Human) CVCL_0336
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Wound healing assay; Anoikis assays
Mechanism Description Upregulation of miR137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma.
Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [22]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MDM2/AR-FkBP5/PHLPP signaling pathway Regulation hsa04115
AKT/ERK signaling pathway Regulation hsa04010
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
SNU398 cells Liver Homo sapiens (Human) CVCL_0077
Skhep1 cells Liver Homo sapiens (Human) CVCL_0525
HA22T cells Liver Homo sapiens (Human) CVCL_7046
SNU423 cells Liver Homo sapiens (Human) CVCL_0366
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 3D Invasion Assay
Mechanism Description miR367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FkBP5 and PHLPP, thus dephosphorylating and inactivating AkT and ERk, to suppress the HCC cell invasion. miR367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FkBP5/PHLPP/(pAkT and pERk) signals to better suppress HCC metastasis.
Key Molecule: Serpin B3 (SERPINB3) [23]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Signal transducer activator transcription 3 (STAT3) [24]
Molecule Alteration Phosphorylation
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell viability Inhibition hsa05200
STAT3 signaling pathway Inhibition hsa04550
In Vitro Model HCCLM3 cells Liver Homo sapiens (Human) CVCL_6832
SMMC7721 cells Uterus Homo sapiens (Human) CVCL_0534
In Vivo Model NOD-SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description Interference lncARSR suppressed liver CSCs expansion and the phosphorylation of the STAT3 molecule was evidently inactivated in both the SMMC7721 si-lncARSR and HCCLM3 si-lncARSR cells.
Key Molecule: Ras association domain-containing protein 1 (RASSF1) [25]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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: Insulin-like growth factor 1 receptor (IGF1R) [26]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
RAS/RAF/ERK signaling pathway Inhibition hsa04010
In Vitro Model Huh-7 cells Liver Homo sapiens (Human) CVCL_0336
T1115 cells Liver Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance.
Key Molecule: Cyclin-G1 (CCNG1) [19]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Liver cancer [ICD-11: 2C12.6]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
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.
Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A) [27]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular cancer [ICD-11: 2C12.4]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
HIF signaling signaling pathway Inhibition hsa04066
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
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description Overexpression of miR-338-3p inhibited HIF-1alpha 3'-UTR luciferase activity and HIF-1alpha protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1alpha overexpression rescued and HIF-1alpha knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1alpha. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1alpha.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [29]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatitis B virus-associated hepatocellular carcinoma [ICD-11: 2C12.7]
 Disease 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
L02 cells Liver Homo sapiens (Human) CVCL_6926
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description HBV infection in HCC cell lines enhances sorafenib resistance. HBV infection in HCC reduces miR-193b expression and increases Mcl-1 expression. miR-193b directly suppresses the expression of Mcl-1 through its 3'-UTRs. miR-193b facilitates sorafenib-induced apoptosis. miR-193b sensitizes HBV-associated HCC cell lines to sorafenib.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [30]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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 blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [31]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
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 blotting analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ADAM10 (a distintegrin and metalloprotease family), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and Sk-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice.
Key Molecule: Serum response factor (SRF) [31]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
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 blotting analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description ADAM10 (a distintegrin and metalloprotease family), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and Sk-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice.
Kidney cancer [ICD-11: 2C90]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Interleukin-6 (IL6) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell cytotoxicity Activation hsa04650
Tumorigenesis Inhibition hsa05200
In Vitro Model 786-O cells Kidney Homo sapiens (Human) CVCL_1051
A498 cells Kidney Homo sapiens (Human) CVCL_1056
Caki-2 cells Kidney Homo sapiens (Human) CVCL_0235
OSRC-2 cells Kidney Homo sapiens (Human) CVCL_1626
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. LncRNA-SRLR directly binds to NF-kB and promotes IL-6 transcription, leading to the activation of STAT3 and the development of sorafenib tolerance.
Key Molecule: LncRNA sorafenib resistance in renal cell carcinoma associated (LNCSRLR) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Sorafenib tolerance Activation hsa00983
In Vitro Model 786-O cells Kidney Homo sapiens (Human) CVCL_1051
A498 cells Kidney Homo sapiens (Human) CVCL_1056
Caki-2 cells Kidney Homo sapiens (Human) CVCL_0235
OSRC-2 cells Kidney Homo sapiens (Human) CVCL_1626
Experiment for
Molecule Alteration		 Microarray assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. LncRNA-SRLR directly binds to NF-kB and promotes IL-6 transcription, leading to the activation of STAT3 and the development of sorafenib tolerance.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Signal transducer activator transcription 3 (STAT3) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Sorafenib tolerance Activation hsa00983
In Vitro Model 786-O cells Kidney Homo sapiens (Human) CVCL_1051
A498 cells Kidney Homo sapiens (Human) CVCL_1056
Caki-2 cells Kidney Homo sapiens (Human) CVCL_0235
OSRC-2 cells Kidney Homo sapiens (Human) CVCL_1626
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. LncRNA-SRLR directly binds to NF-kB and promotes IL-6 transcription, leading to the activation of STAT3 and the development of sorafenib tolerance.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytochrome P450 family 1 subfamily B member1 (CYP1B1) [19]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Kidney cancer [ICD-11: 2C90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model 769-P cells Kidney Homo sapiens (Human) CVCL_1050
786-O cells Kidney Homo sapiens (Human) CVCL_1051
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-27b [19]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Kidney cancer [ICD-11: 2C90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model 769-P cells Kidney Homo sapiens (Human) CVCL_1050
786-O cells Kidney Homo sapiens (Human) CVCL_1051
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cyclin-G1 (CCNG1) [19]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Kidney cancer [ICD-11: 2C90.1]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
miR27b/CCNG1/p53 signaling pathway Regulation hsa05206
In Vitro Model 769-P cells Kidney Homo sapiens (Human) CVCL_1050
786-O cells Kidney Homo sapiens (Human) CVCL_1051
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description miR-27b synergizes with anticancer drugs througth enhancing anticancer drug-induced cell death which due to p53 activation and CYP1B1 suppression.
ICD-13: Digestive system diseases
Click to Show/Hide the Resistance Disease of This Class
Nonalcoholic fatty liver disease [ICD-11: DB92]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
Key Molecule: TNF alpha induced protein 8 (TNFAIP8) [5]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Hepatic Steatosis [ICD-11: DB92.Y]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/mTOR signaling pathway Inhibition hsa04150
In Vitro Model HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
SK-Hep1 cells Ascites Homo sapiens (Human) CVCL_0525
PLC/PRF/5 cells Liver Homo sapiens (Human) CVCL_0485
In Vivo Model C57BL/6J mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; RT/qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins.
References
Ref 1 MiR-374b re-sensitizes hepatocellular carcinoma cells to sorafenib therapy by antagonizing PKM2-mediated glycolysis pathway. Am J Cancer Res. 2019 Apr 1;9(4):765-778. eCollection 2019.
Ref 2 Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012 May 31;119(22):5133-43. doi: 10.1182/blood-2011-06-363960. Epub 2012 Feb 24.
Ref 3 Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. Oncogene. 2017 Apr 6;36(14):1965-1977. doi: 10.1038/onc.2016.356. Epub 2016 Nov 14.
Ref 4 MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013 Aug;58(2):629-41. doi: 10.1002/hep.26369. Epub 2013 Jun 25.
Ref 5 TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation .Cell Death Dis. 2020 Mar 9;11(3):178. doi: 10.1038/s41419-020-2369-4. 10.1038/s41419-020-2369-4
Ref 6 Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res. 2014 Oct;12(10):1377-87. doi: 10.1158/1541-7786.MCR-13-0636. Epub 2014 May 29.
Ref 7 Mutation position within evolutionary subclonal architecture in AML. Semin Hematol. 2014 Oct;51(4):273-81. doi: 10.1053/j.seminhematol.2014.08.004. Epub 2014 Aug 7.
Ref 8 Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Clin Cancer Res. 2013 Oct 15;19(20):5758-68. doi: 10.1158/1078-0432.CCR-13-1323. Epub 2013 Aug 22.
Ref 9 miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway. Gene. 2019 Jul 30;707:78-85. doi: 10.1016/j.gene.2019.05.015. Epub 2019 May 7.
Ref 10 LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2019 May 3;38(1):183. doi: 10.1186/s13046-019-1177-0.
Ref 11 Long noncoding RNA NEAT1 suppresses sorafenib sensitivity of hepatocellular carcinoma cells via regulating miR-335-c-Met. J Cell Physiol. 2019 Apr 1. doi: 10.1002/jcp.27567. Online ahead of print.
Ref 12 The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. Cell Death Dis. 2018 Jan 5;9(1):4. doi: 10.1038/s41419-017-0076-6.
Ref 13 High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models. Lab Invest. 2018 Jan;98(1):95-105. doi: 10.1038/labinvest.2017.107. Epub 2017 Oct 16.
Ref 14 In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis. Clin Cancer Res. 2017 Jul 15;23(14):3953-3965. doi: 10.1158/1078-0432.CCR-16-1464. Epub 2017 Jan 17.
Ref 15 Long non-coding RNA TUC338 is functionally involved in sorafenib-sensitized hepatocarcinoma cells by targeting RASAL1. Oncol Rep. 2017 Jan;37(1):273-280. doi: 10.3892/or.2016.5248. Epub 2016 Nov 15.
Ref 16 microRNA-19a-3p promotes tumor metastasis and chemoresistance through the PTEN/Akt pathway in hepatocellular carcinoma. Biomed Pharmacother. 2018 Sep;105:1147-1154. doi: 10.1016/j.biopha.2018.06.097. Epub 2018 Jun 21.
Ref 17 miR 222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma. Int J Oncol. 2014 Oct;45(4):1537-46. doi: 10.3892/ijo.2014.2577. Epub 2014 Aug 4.
Ref 18 MicroRNA-375 represses tumor angiogenesis and reverses resistance to sorafenib in hepatocarcinoma .Cancer Gene Ther. 2021 Feb;28(1-2):126-140. doi: 10.1038/s41417-020-0191-x. Epub 2020 Jul 3. 10.1038/s41417-020-0191-x
Ref 19 miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression. Cell Res. 2015 Apr;25(4):477-95. doi: 10.1038/cr.2015.23. Epub 2015 Feb 20.
Ref 20 miR 378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRBeta and c Raf. Mol Med Rep. 2018 Mar;17(3):4581-4588. doi: 10.3892/mmr.2018.8390. Epub 2018 Jan 8.
Ref 21 Upregulation of miR-137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma. Oncol Rep. 2017 Apr;37(4):2071-2078. doi: 10.3892/or.2017.5498. Epub 2017 Mar 10.
Ref 22 The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals. EBioMedicine. 2016 Oct;12:55-67. doi: 10.1016/j.ebiom.2016.07.013. Epub 2016 Jul 14.
Ref 23 MiR-122 Targets SerpinB3 and Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma. J Clin Med. 2019 Feb 1;8(2):171. doi: 10.3390/jcm8020171.
Ref 24 lncARSR promotes liver cancer stem cells expansion via STAT3 pathway. Gene. 2019 Mar 1;687:73-81. doi: 10.1016/j.gene.2018.10.087. Epub 2018 Oct 31.
Ref 25 miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression. Cancer Sci. 2016 Sep;107(9):1256-62. doi: 10.1111/cas.13006. Epub 2016 Sep 2.
Ref 26 MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. Cancer Lett. 2016 Feb 28;371(2):171-81. doi: 10.1016/j.canlet.2015.11.034. Epub 2015 Dec 3.
Ref 27 MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1Alpha. PLoS One. 2014 Dec 22;9(12):e115565. doi: 10.1371/journal.pone.0115565. eCollection 2014.
Ref 28 MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma. Liver Int. 2015 Mar;35(3):1077-86. doi: 10.1111/liv.12636. Epub 2014 Jul 21.
Ref 29 Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib. Cancer Lett. 2014 Oct 1;352(2):245-52. doi: 10.1016/j.canlet.2014.07.004. Epub 2014 Jul 14.
Ref 30 MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technol Cancer Res Treat. 2014 Feb;13(1):77-86. doi: 10.7785/tcrt.2012.500364. Epub 2013 Jul 11.
Ref 31 MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem. 2009 Nov 13;284(46):32015-27. doi: 10.1074/jbc.M109.016774. Epub 2009 Sep 2.

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