Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases.
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.
['Yamaguchi|Takashi|T|', 'Yoshida|Katsunori|K|', 'Murata|Miki|M|', 'Matsuzaki|Koichi|K|']
D000818:Animals D000998:Antiviral Agents D006528:Carcinoma, Hepatocellular D002472:Cell Transformation, Viral D016174:Hepacivirus D019698:Hepatitis C, Chronic D054884:Host-Pathogen Interactions D006801:Humans D048031:JNK Mitogen-Activated Protein Kinases D008099:Liver D008103:Liver Cirrhosis D008113:Liver Neoplasms D010766:Phosphorylation D017346:Protein Serine-Threonine Kinases D000077293:Receptor, Transforming Growth Factor-beta Type I D018125:Receptors, Transforming Growth Factor beta D015398:Signal Transduction D051900:Smad3 Protein
Smad3 phospho-isoform signaling Hepatocellular carcinoma Chronic inflammation Hepatitis C virus Transforming growth factor β c-Jun N-terminal kinase