Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma.
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.
Miki Murata, Katsunori Yoshida, Takashi Yamaguchi, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
Miki
M
Murata
Miki Murata, Katsunori Yoshida, Takashi Yamaguchi, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
Katsunori
K
Yoshida
Miki Murata, Katsunori Yoshida, Takashi Yamaguchi, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
Takashi
T
Yamaguchi
Miki Murata, Katsunori Yoshida, Takashi Yamaguchi, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
Koichi
K
Matsuzaki
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002472:Cell Transformation, Viral; D019694:Hepatitis B, Chronic / Q000150:complications*; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D048031:JNK Mitogen-Activated Protein Kinases
Chronic viral hepatitis; Fibro-carcinogenesis; Hepatocellular carcinoma; Phosphorylation; Smad3; Transforming growth factor-β