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

Hepatology. 2010 Aug;52(2):480-92. doi: 10.1002/hep.23697.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COP9 Signalosome Complex
  • Carcinoma, Hepatocellular / virology*
  • DNA Repair*
  • Hepacivirus*
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Liver Neoplasms / virology*
  • Mice
  • Mice, Transgenic
  • Nitric Oxide / physiology*
  • Oxidation-Reduction
  • Peptide Hydrolases / physiology*
  • STAT3 Transcription Factor / physiology*
  • Signal Transduction*


  • Intracellular Signaling Peptides and Proteins
  • STAT3 Transcription Factor
  • Nitric Oxide
  • Peptide Hydrolases
  • Cops5 protein, mouse
  • COP9 Signalosome Complex