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


CONCLUSIONS
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.
Matsuzaki
Koichi
K
Department of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Osaka, Japan. matsuzak@takii.kmu.ac.jp
Murata
Miki
M
Yoshida
Katsunori
K
Sekimoto
Go
G
Uemura
Yoshiko
Y
Sakaida
Noriko
N
Kaibori
Masaki
M
Kamiyama
Yasuo
Y
Nishizawa
Mikio
M
Fujisawa
Junichi
J
Okazaki
Kazuichi
K
Seki
Toshihito
T
D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology* / Q000209:etiology; D004261:DNA Replication; D018450:Disease Progression; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000503:physiopathology*; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000209:etiology; D015995:Prevalence; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000509:alpha-Fetoproteins / Q000032:analysis
D012367:RNA, Viral; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000509:alpha-Fetoproteins; D013936:Thymidine