Exploring the Role of β-catenin Signaling in Hepatitis B Virus Regulation and Hepatocellular Carcinoma

Hepatitis B virus (HBV) is a devastating pathogen which kills up to 1 million people every year. Chronic carriers have no curative treatment options and suffer from liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). A greater understanding of the in vivo regulation of HBV biosynthesis and HBV-associated HCC is important to developing effective therapies for HBV infected individuals. The current study seeks to elucidate the role of β-catenin in this regulation. Liver-specific β-catenin-null HBV transgenic mice reveal that β-catenin regulates HBV biosynthesis in vivo, as these mice exhibit a 3-fold reduction in viral replication and a major change in the distribution of viral biosynthesis across the liver lobule. Cell culture studies reveal that β-catenin regulates the transcription of viral pregenomic RNA and subsequent replication, primarily through the nuclear receptors liver receptor homolog 1 and farnesoid X receptor α. Additional post-transcriptional regulation of HBV biosynthesis by β-catenin may also occur. Liver-specific Apc- and Pten-null HBV transgenic mice are useful in vivo models of HCC in the context of viral replication. Pten-null mice develop HCC with heterogeneous phenotypes in regard to both HBV biosynthesis and β-catenin signaling despite sharing the same oncogenic mutation. Apc-null mice develop HCC with high β-catenin signaling but still heterogeneous phenotypes in regard to HBV biosynthesis and other transcriptional profiles. Dual Pten-null Apc-null mice develop HCC with generally intermediate, but still heterogeneous, phenotypes. These results indicate that the cell of origin in the liver lobule plays an important role in determining tumor phenotype in addition to the specific initiating mutation, which carries important implications for the development of effective therapies for individual HCC patients.