Early Chronic Inflammation and Subsequent Somatic Mutations Shift Phospho-Smad3 Signaling from Tumor-Suppression to Fibro-Carcinogenesis in Human Chronic Liver Diseases

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide [1]. HCC is strongly associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, which are implicated in about 80% of HCCs in certain geographic area [2]. Risk of HCC is increased 5to 15-fold in chronic HBV carriers [1] and 11.5to 17-fold in HCV-infected patients [3]. In addition, epidemiological studies have shown that chronic inflammation of the liver predisposes individuals to HCC. Most HCCs are associated with severe fibrosis or cirrhosis caused by unresolved inflammation. Both HBV and HCV show a wide spectrum of clinical manifestations, ranging from a healthy carrier state to chronic hepatitis, cirrhosis and HCC. Notably, HCC occurs less often in chronic viral hepatitis with‐ out cirrhosis. As liver fibrosis progresses from chronic hepatitis to cirrhosis, HCC occurrence increases [4]. Thus, unresolved inflammation with long-term viral infection leads to HCC associated with cirrhosis. Approaches to understanding how human HCC develops in chronic inflammatory liver diseases should therefor focus on molecular mechanisms shared between liver fibrosis and carcinogenesis (fibro-carcinogenesis).