Novel Mouse Models of Hepatocarcinogenesis with Stepwise Accumulation of Genetic Alterations

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Various risk factors are involved in hepatocarcinogenesis. Among them, chronic inflammation, including chronic hepatitis and cirrhosis mainly caused by hepatitis B virus and/or hepatitis C virus infection, plays an important role in HCC development. On the other hand, comprehensive genetic analyses of HCC using whole genome and exome sequencing revealed that cancer cells possess a large number of somatic mutations, suggesting that a wide variety of genetic alterations and the resultant dysregulated molecular pathways contribute to the development of HCC. Activation-induced cytidine deaminase (AID) is a nucleotide-editing enzyme, and aberrant expression of AID induced by inflammatory responses contributes to hepatocarcinogenesis via the accumulation of genetic alterations in various tumor-related genes. Constitutive expression of AID in hepatocyte-lineage cells provides novel mouse models that recapitulate the tumorigenesis of human HCC through stepwise accumulation of genetic alterations.