c-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide–dependent impairment of oxidative DNA repair

Authors

  • Keigo Machida,

    Corresponding author
    1. Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA
    2. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, University of Southern California, Keck School of Medicine, Los Angeles, CA
    • Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 211 Zonal Avenue, Los Angeles, CA 90033
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    • fax: 323-442-1721

  • Hidekazu Tsukamoto,

    1. Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA
    2. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, University of Southern California, Keck School of Medicine, Los Angeles, CA
    3. Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA
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  • Jian-Chang Liu,

    1. Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA
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  • Yuan-Ping Han,

    1. Surgery, University of Southern California, Keck School of Medicine, Los Angeles, CA
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  • Sugantha Govindarajan,

    1. Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA
    2. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, University of Southern California, Keck School of Medicine, Los Angeles, CA
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  • Michael M. C. Lai,

    1. Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA
    2. National Chun Kung University, Tainan, Taiwan
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  • Shizuo Akira,

    1. Osaka University, Osaka, Japan
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  • Jing-hsiung James Ou

    1. Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA
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  • Potential conflict of interest: Nothing to report.

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-α, 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. Conclusion: 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. Hepatology 2010

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