RGD Reference Report - Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events. - Rat Genome Database

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Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events.

Authors: Higgs, M R  Lerat, H  Pawlotsky, J-M 
Citation: Higgs MR, etal., Oncogene. 2013 Sep 26;32(39):4683-93. doi: 10.1038/onc.2012.484. Epub 2012 Oct 29.
RGD ID: 14695017
Pubmed: PMID:23108410   (View Abstract at PubMed)
DOI: DOI:10.1038/onc.2012.484   (Journal Full-text)

Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of hepatocellular carcinoma (HCC), although the underlying mechanisms are unclear. The c-Myc oncogene contributes to the genesis of many types of cancers, including HCC, partly via the induction of genetic damage and the inhibition of the cellular response to genotoxic stress. Here, we show a previously undiscovered mechanistic link between HCV infection and enhanced c-Myc expression. c-Myc expression was augmented in non-tumoral liver tissues from HCV-infected individuals with or without HCC and in hepatocyte cell lines harboring an HCV replicon and the infectious HCV strain JFH1. Increased c-Myc expression was confirmed in vivo in a transgenic murine model expressing the entire HCV open reading frame, demonstrating a direct role for HCV protein expression in c-Myc induction. Mechanistically, activation of Akt by the HCV non-structural protein NS5A, and the subsequent stabilization of the transcription factor β-catenin, was demonstrated to be responsible for activation of the c-Myc promoter, and for increased c-Myc transcription. β-Catenin-dependent c-Myc expression in this context led to increased production of reactive oxygen species, mitochondrial perturbation, enhanced DNA damage and aberrant cell-cycle arrest. Together, these data provide a novel insight into the mechanisms involved in HCV-associated HCCs, strongly suggesting that c-Myc has a crucial contributory role in this process.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hepatitis C  IEP 14695017mRNA and protein:increased expression:liverRGD 
hepatitis C  ISOMYC (Homo sapiens)14695017; 14695017mRNA and protein:increased expression:liverRGD 

Objects Annotated

Genes (Rattus norvegicus)
Myc  (MYC proto-oncogene, bHLH transcription factor)

Genes (Mus musculus)
Myc  (myelocytomatosis oncogene)

Genes (Homo sapiens)
MYC  (MYC proto-oncogene, bHLH transcription factor)


Additional Information