title: Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U955, Institut Mondor de Recherche Biomédicale, Créteil, France.
authors.forename: M R
authors.initials: MR
authors.lastname: Higgs
authors.forename: H
authors.initials: H
authors.lastname: Lerat
authors.forename: J-M
authors.initials: JM
authors.lastname: Pawlotsky
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000209:etiology / Q000821:virology; D002467:Cell Nucleus / Q000737:chemistry; D002472:Cell Transformation, Viral / Q000235:genetics*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D005260:Female; D016259:Genes, myc; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D022781:Hepatocytes / Q000737:chemistry / Q000648:ultrastructure; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000209:etiology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D016366:Open Reading Frames / Q000235:genetics; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics; D017382:Reactive Oxygen Species; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004272:DNA, Mitochondrial; D009363:Neoplasm Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D012367:RNA, Viral; D017382:Reactive Oxygen Species; D017361:Viral Nonstructural Proteins; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C489427:MYC protein, human; C489428:Myc protein, mouse; C514862:Akt1 protein, mouse; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase