Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C

Takashi Yamaguchi; Koichi Matsuzaki; Ryosuke Inokuchi; Rinako Kawamura; Katsunori Yoshida; Miki Murata; Junichi Fujisawa; Nobuyoshi Fukushima; Michio Sata; Masayoshi Kage; Osamu Nakashima; Akihiro Tamori; Norifumi Kawada; Koichi Tsuneyama; Steven Dooley; Toshihito Seki; Kazuichi Okazaki

doi:10.1111/hepr.12082

Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C

Hepatol Res. 2013 Dec;43(12):1327-42. doi: 10.1111/hepr.12082. Epub 2013 Mar 4.

Authors

Takashi Yamaguchi¹, Koichi Matsuzaki, Ryosuke Inokuchi, Rinako Kawamura, Katsunori Yoshida, Miki Murata, Junichi Fujisawa, Nobuyoshi Fukushima, Michio Sata, Masayoshi Kage, Osamu Nakashima, Akihiro Tamori, Norifumi Kawada, Koichi Tsuneyama, Steven Dooley, Toshihito Seki, Kazuichi Okazaki

Affiliation

¹ Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan.

PMID: 23458062
DOI: 10.1111/hepr.12082

Abstract

Aim: 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.

Conclusion: 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.

Keywords: Smad; hepatocarcinogenesis; liver fibrosis; transforming growth factor-β.