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Phosphorylated S mad2 and S mad3 signaling: Shifting between tumor suppression and fibro‐carcinogenesis in chronic hepatitis C
Author(s) -
Yamaguchi Takashi,
Matsuzaki Koichi,
Inokuchi Ryosuke,
Kawamura Rinako,
Yoshida Katsunori,
Murata Miki,
Fujisawa Junichi,
Fukushima Nobuyoshi,
Sata Michio,
Kage Masayoshi,
Nakashima Osamu,
Tamori Akihiro,
Kawada Norifumi,
Tsuneyama Koichi,
Dooley Steven,
Seki Toshihito,
Okazaki Kazuichi
Publication year - 2013
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12082
Subject(s) - carcinogenesis , hepatocellular carcinoma , cancer research , hepatitis c virus , hepatitis c , signal transduction , medicine , fibrosis , biology , immunology , cancer , virus , biochemistry
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 S mad2 and S mad3 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‐ S mad2/3 positivity of 100 patients in different stages of HCV ‐related chronic liver disease. To examine changes in phospho‐ S mad2/3 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‐ S mad 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.