Distinct phenotypic spectra of hepatocellular carcinoma in liver-specific tumor suppressor-deficient hepatitis B virus transgenic mice

Abstract

The hepatitis B virus (HBV) transgenic mouse model was used to interrogate the origins of HCC heterogeneity. HBV biosynthesis was used as a marker of liver tumor heterogeneity. Principal component and correlation analysis of HBV and cellular transcript levels demonstrated major differences within and between the gene expression profiles of Apc-deficient, Apc-deficient Pten-deficient, and Pten-deficient HCC. Hence, both oncogenic stimuli and zonal hepatocyte properties determine heterogeneous HCC phenotypes. Additionally, Apc-deficient HCC display decreased expression of Apob, Otc and Tet2 relative to Pten-deficient HCC and control liver tissue suggesting their gene products may represent markers of Apc-deficient HCC. A subset of human HCC with mutations in the β-catenin gene (CTNNB1) displayed a gene expression profile similar to that observed in the mouse Apc-deficient HCC indicating this model of liver cancer may be useful for interrogating the molecular properties of these tumors and their potential therapeutic vulnerabilities.

Keywords: Adenomatous polyposis coli (Apc); Hepatitis B virus (HBV); Hepatocellular carcinoma (HCC); Hepatocyte phenotype; Liver lobule zonation; Phosphatase and tensin homolog (Pten).