| セッション情報 | The 2nd JSGE International Topic Conference1）Inflammation and Hepatocellular Carcinoma |
|---|---|
| タイトル | IT1-3：Reversible Phospho-Smad Signaling between Tumor-suppression and Fibro-carcinogenesis in Human Chronic Liver Diseases |
| 演者 | Matsuzaki Koichi（Department of Gastroenterology and Hepatology, Kansai Medical University, Japan） |
| 共同演者 | Seki Toshihito（Department of Gastroenterology and Hepatology, Kansai Medical University, Japan）, Okazaki Kazuichi（Department of Gastroenterology and Hepatology, Kansai Medical University, Japan） |
| 抄録 | Clinical observations suggest that chronic inflammation associated with hepatitis B or C virus（HBV or HCV）infection simultaneously induces hepatic fibrosis and carcinogenesis（fibro-carcinogenesis）. Conversely, anti-viral therapy for HBV or HCV can suppress liver fibrosis and inflammation in patients with mild fibrosis. Furthermore, these patients have marked reductions in hepatocellular carcinoma（HCC）occurrence. However, patients with advanced fibrosis have real risks of HCC occurrence despite effective anti-viral therapy. Perturbation of hepatocytic transforming growth factor（TGF）-beta signaling by pro-inflammatory cytokines can promote fibro-carcinogenesis. Smads, central mediators carrying signals from receptors for TGF-beta super-family members to the nucleus, are modular proteins with conserved Mad-homology（MH）1, intermediate linker, and MH2 domains. TGF-beta and pro-inflammatory cytokines differentially phosphorylate Smad3 to create 2 phosphoisoforms：COOH-terminally phosphorylated Smad3（pSmad3C）and linker-phosphorylated Smad3（pSmad3L）. In our session, we will speak how chronic inflammation affects liver fibrosis and HCC development, focusing on changes in hepatocytic domain-specific phospho-Smad3 signaling before and after anti-viral therapy. During progression of chronic liver diseases, chronic inflammation shifts hepatocytic Smad3 signaling from tumor-suppressive pSmad3C to fibro-carcinogenic pSmad3L branch, accelerating liver fibrosis and increasing risk of HCC. In patients with mild fibrosis after anti-viral therapy, suppression of inflammation permits reduction of fibrosis and HCC incidence by successfully reversing phospho-Smad3 signaling from fibro-carcinogenic pSmad3L to tumor-suppressive pSmad3C. However, HCC develops particularly in patients with advanced liver fibrosis, where an inflammation-independent process of fibro-carcinogenesis, possibly caused by genetic or epigenetic alteration, has already begun before anti-viral therapy. |
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