Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma

Hepatology. 2007 Jul;46(1):48-57. doi: 10.1002/hep.21672.


Many patients with chronic hepatitis caused by hepatitis C virus (HCV) infection develop liver fibrosis with high risk for hepatocellular carcinoma (HCC), but the mechanism underling this process is unclear. Conversely, transforming growth factor beta (TGF-beta) activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), which convert the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Whereas the TbetaRI/pSmad3C pathway suppresses epithelial cell growth by upregulating p21(WAF1) transcription, JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, partly, by upregulating plasminogen activator inhibitor 1 (PAI-1). We studied the domain-specific Smad3 phosphorylation in biopsy specimens representing chronic hepatitis, cirrhosis, or HCC from 100 patients chronically infected with HCV, and correlated Smad3 phosphorylation with clinical course. As HCV-infected livers progressed from chronic hepatitis through cirrhosis to HCC, hepatocytic pSmad3L/PAI-1 increased with fibrotic stage and necroinflammatory grade, and pSmad3C/p21(WAF1) decreased. Of 14 patients with chronic hepatitis C with strong hepatocytic pSmad3L positivity, 8 developed HCC within 12 years; only 1 of 12 showing little pSmad3L positivity developed HCC. We further sought molecular mechanisms in vitro. JNK activation by the pro-inflammatory cytokine interleukin-1beta stimulated the pSmad3L/PAI-1 pathway in facilitating hepatocytic invasion, in the meantime reducing TGF-beta-dependent tumor-suppressive activity by the pSmad3C/p21(WAF1) pathway.

Conclusion: These results indicate that chronic inflammation associated with HCV infection shifts hepatocytic TGF-beta signaling from tumor-suppression to fibrogenesis, accelerating liver fibrosis and increasing risk for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Carcinoma, Hepatocellular / epidemiology*
  • Carcinoma, Hepatocellular / etiology
  • DNA Replication
  • Disease Progression
  • Hepatitis C, Chronic / complications*
  • Hepatitis C, Chronic / epidemiology
  • Hepatitis C, Chronic / pathology
  • Humans
  • Inflammation / etiology*
  • Liver / pathology
  • Liver Cirrhosis / epidemiology
  • Liver Cirrhosis / physiopathology*
  • Liver Neoplasms / epidemiology*
  • Liver Neoplasms / etiology
  • Prevalence
  • RNA, Viral / blood
  • RNA, Viral / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Smad3 Protein / metabolism
  • Thymidine / metabolism
  • Transforming Growth Factor beta / physiology*
  • alpha-Fetoproteins / analysis


  • RNA, Viral
  • Smad3 Protein
  • Transforming Growth Factor beta
  • alpha-Fetoproteins
  • Thymidine