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World J Gastroenterol. Nov 7, 2014; 20(41): 15018-15027
Published online Nov 7, 2014. doi: 10.3748/wjg.v20.i41.15018
Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma
Miki Murata, Katsunori Yoshida, Takashi Yamaguchi, Koichi Matsuzaki
Miki Murata, Katsunori Yoshida, Takashi Yamaguchi, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan
Author contributions: All the authors contributed to this manuscript.
Correspondence to: Miki Murata, MD, Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan. muratami@takii.kmu.ac.jp
Telephone: +81-6-69921000 Fax: +81-6-69975490
Received: December 26, 2013
Revised: March 8, 2014
Accepted: July 15, 2014
Published online: November 7, 2014
Abstract

Epidemiological and clinical data point to a close association between chronic hepatitis B virus infection or chronic hepatitis C virus infection and development of hepatocellular carcinoma (HCC). HCC develops over several decades and is associated with fibrosis. This sequence suggests that persistent viral infection and chronic inflammation can synergistically induce liver fibrosis and hepatocarcinogenesis. The transforming growth factor-β (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes and contributes to hepatic fibro-carcinogenesis under inflammatory microenvironments during chronic liver diseases. The biological activities of TGF-β are initiated by the binding of the ligand to TGF-β receptors, which phosphorylate Smad proteins. TGF-β type I receptor activates Smad3 to create COOH-terminally phosphorylated Smad3 (pSmad3C), while pro-inflammatory cytokine-activated kinases phosphorylates Smad3 to create the linker phosphorylated Smad3 (pSmad3L). During chronic liver disease progression, virus components, together with pro-inflammatory cytokines and somatic mutations, convert the Smad3 signal from tumor-suppressive pSmad3C to fibro-carcinogenic pSmad3L pathways, accelerating liver fibrosis and increasing the risk of HCC. The understanding of Smad3 phosphorylation profiles may provide new opportunities for effective chemoprevention and personalized therapy for patients with hepatitis virus-related HCC in the future.

Keywords: Chronic viral hepatitis, Transforming growth factor-β, Smad3, Phosphorylation, Fibro-carcinogenesis, Hepatocellular carcinoma

Core tip: Chronic hepatitis B and C infections are major causes of cirrhosis and hepatocellular carcinoma (HCC). Most patients with persistent viral infection remain asymptomatic, while some patients have poor prognosis and develop HCC. Therefore, identifying persons at high-HCC risk among chronic hepatitis patients is crucial for preventing HCC. Analyses of domain-specific phosphorylation of Smad3 in liver specimens can be helpful to understand the stages of diseases and might represent a marker to predict HCC development.