Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and chronic hepatitis B virus (HBV) infection is the most important risk factor of HCC. However, it remains unclear whether HBV plays any direct role in carcinogenesis. We have established two independent transgenic mouse lines expressing a mutant HBV (“preS2 mutant”) that is found at a significant higher frequency in people with HCC than those without. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice developed hepatocellular neoplasms, including HCC. We also found a significant increase in hepatocarcinogenesis independent of inflammation in a transgenic mouse line expressing wildtype HBV. The significant increase of HCC incidence in all three HBV transgenic lines argues that HBV contributes directly to the development of HCC in the absence of chronic inflammation. Endoplasmic reticulum stress-induced unfolded protein response activation and β-catenin truncation/mutation were found in the HCC samples, which may contribute to the hepatocacinogenesis. To screen other candidate genes critical in the HCC development, we performed mouse whole genome microarray analysis and identified a group of genes whose expression levels increased in the livers of the HBV transgenic mice and often further increased in HCC compared to that of the non-transgenic littermates. Using quantitative RT-PCR, we confirmed the expression pattern in 8 out of 10 selected genes that are known to involve in the control of cell survival/proliferation, mobility and intercellular signaling. Among the eight genes, Fabp5 encodes a retinoic acid-binding protein that is known to be overexpressed in various types of human tumors, including HCC, and is implicated in tumor cell survival and proliferation. We also found that Fabp5 is highly expressed in HCC cell lines and in the HCC of our HBV transgenic mice by Western Blot. Immunohistochemistry/immunofluorescence staining confirmed that hepatocytes in HCC overexpress Fabp5. More importantly, Fabp5 expression is significantly elevated in the liver of 4-month old HBV transgenic mice long before HCC development. Therefore our findings suggest that HBV expression may disrupt regulation of proteins important for cell survival and proliferation and contribute directly to hepatocarcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4814. doi:1538-7445.AM2012-4814

©2012 American Association for Cancer Research
2012