title: Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases.
abstract: The risk of hepatocellular carcinoma (HCC) development increases as hepatitis virus C (HCV)-related liver diseases progress, especially in patients with active inflammation. Insight into hepatic carcinogenesis have emerged from recent detailed analyses of transforming growth factor-β and c-Jun-N-terminal kinase signaling processes directed by multiple phosphorylated (phospho)-isoforms of a Smad3 mediator. In the course of HCV-related chronic liver diseases, chronic inflammation and host genetic/epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis, increasing the risk of HCC. Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus. After undergoing successful antiviral therapy, patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression. Even after HCV clearance, however, patients with cirrhosis could still develop HCC because of sustained, intense carcinogenic Smad3 phospho-isoform signaling that is possibly caused by genetic or epigenetic alterations. Smad3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC.
authors.affiliation: Takashi Yamaguchi, Katsunori Yoshida, Miki Murata, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Takashi Yamaguchi, Katsunori Yoshida, Miki Murata, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Takashi Yamaguchi, Katsunori Yoshida, Miki Murata, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Murata
authors.affiliation: Takashi Yamaguchi, Katsunori Yoshida, Miki Murata, Koichi Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka 570-8506, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuzaki
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D002472:Cell Transformation, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Chronic inflammation; Hepatitis C virus; Hepatocellular carcinoma; Smad3 phospho-isoform signaling; Transforming growth factor β; c-Jun N-terminal kinase