Published online Sep 21, 2014. doi: 10.3748/wjg.v20.i35.12381
Revised: February 22, 2014
Accepted: May 29, 2014
Published online: September 21, 2014
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.
Core tip: The risk of hepatocellular carcinoma (HCC) development increases in patients persistently infected with hepatitis viruses, especially in patients with active viral replication and inflammation. Our model suggests that the chronic inflammatory state and the hepatitis viruses themselves act in concert with genetic or epigenetic alterations to worsen human liver diseases by promoting hepatic carcinogenesis. The affected hepatocytes are subject to such interactions until their descendants acquire other genetic or epigenetic alterations. Even after the withdrawal of promoters such as chronic inflammation and hepatitis viruses, the hepatocytes could retain proliferative phenotypes, enabling some pre-neoplastic hepatocytes to develop into HCC.