title: c-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide-dependent impairment of oxidative DNA repair.
abstract: Hepatocellular carcinoma (HCC) occurs in a significant number of patients with hepatitis C virus (HCV) infection. HCV causes double-strand DNA breaks and enhances the mutation frequency of proto-oncogenes and tumor suppressors. However, the underlying mechanisms for these oncogenic events are still elusive. Here, we studied the role of c-Jun, signal transducer and activator of transcription 3 (STAT3), and nitric oxide (NO) in spontaneous and diethylnitrosamine (DEN)-initiated and/or phenobarbital (Pb)-promoted HCC development using HCV core transgenic (Tg) mice. The viral core protein induces hepatocarcinogenesis induction as a tumor initiator under promotion by Pb treatment alone. Conditional knockout of c-jun and stat3 in hepatocytes achieves a nearly complete, additive effect on prevention of core-induced spontaneous HCC or core-enhanced HCC incidence caused by DEN/Pb. Core protein induces hepatocyte proliferation and the expression of inflammatory cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1) and inducible NO synthase (iNOS); the former is dependent on c-Jun and STAT3, and the latter on c-Jun. Oxidative DNA damage repair activity is impaired by the HCV core protein due to reduced DNA glycosylase activity for the excision of 8-oxo-2'-deoxyguanosine. This impairment is abrogated by iNOS inhibition or c-Jun deficiency, but aggravated by the NO donor or iNOS-inducing cytokines. The core protein also suppresses apoptosis mediated by Fas ligand because of c-Jun-dependent Fas down-regulation.
  
  
  CONCLUSIONS
  These results indicate that the HCV core protein potentiates chemically induced HCC through c-Jun and STAT3 activation, which in turn, enhances cell proliferation, suppresses apoptosis, and impairs oxidative DNA damage repair, leading to hepatocellular transformation.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA. kmachida@usc.edu
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Jian-Chang
authors.initials: JC
authors.lastname: Liu
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Han
authors.forename: Sugantha
authors.initials: S
authors.lastname: Govindarajan
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Jing-Hsiung James
authors.initials: JH
authors.lastname: Ou
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D004260:DNA Repair; D016174:Hepacivirus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000502:physiology*; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex