title: Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C.
abstract: OBJECTIVE
  Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-β signaling. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling.
  
  
  METHODS
  We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group).
  
  
  RESULTS
  Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling.
  
  
  CONCLUSIONS
  HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance.
authors: Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan.
authors: Takashi
authors: T
authors: Yamaguchi
authors: Koichi
authors: K
authors: Matsuzaki
authors: Ryosuke
authors: R
authors: Inokuchi
authors: Rinako
authors: R
authors: Kawamura
authors: Katsunori
authors: K
authors: Yoshida
authors: Miki
authors: M
authors: Murata
authors: Junichi
authors: J
authors: Fujisawa
authors: Nobuyoshi
authors: N
authors: Fukushima
authors: Michio
authors: M
authors: Sata
authors: Masayoshi
authors: M
authors: Kage
authors: Osamu
authors: O
authors: Nakashima
authors: Akihiro
authors: A
authors: Tamori
authors: Norifumi
authors: N
authors: Kawada
authors: Koichi
authors: K
authors: Tsuneyama
authors: Steven
authors: S
authors: Dooley
authors: Toshihito
authors: T
authors: Seki
authors: Kazuichi
authors: K
authors: Okazaki
keywords: Smad; hepatocarcinogenesis; liver fibrosis; transforming growth factor-β