Hepatitis B Virus Promotes Hepatocellular Carcinoma Development by Activating GP73 to Repress the Innate Immune Response

Background Hepatitis B virus (HBV) causes acute and chronic infection in the clinic. Hepatocellular carcinoma (HCC) is closely linked to HBV infection. Serum Golgi protein 73 (GP73) increases during HBV infection. However, the role of GP73 during HBV infection and the occurrence of HBV-related HCC is still poorly understood. Methods The underlying role of HBV-induced GP73 in regulating HCC development was investigated in this study. GP73 expression in HBV-related clinical HCC tissues and in HBV infected hepatoma cells and primary human hepatocytes were evaluated by immunohistochemistry, ELISA, Western Blotting and Quantitative real-time PCR (QRT-PCR) analysis. GP73 mediated tumorigenesis were detected by flow cytometry, QRT-PCR, xenograft nude mice and sphere formation assay. The effects of GP73 and HBV infection on host's innate immune responses in hepatocytes were further investigated by Western Blotting and Quantitative real-time PCR (QRT-PCR) analysis. Results Initially, we discovered that HBV-positive HCC tissues had significantly higher expression of GP73. Ectopic expression of the HBV gene could induce GP73 expression in primary human hepatocytes and hepatoma cells in vitro. In addition, we discovered that GP73 promotes HCC in both normal liver cells and hepatoma cells. We also found that ectopic expression of HBV genes increases GP73 expression, suppressing the host's innate immune responses in hepatocytes. Conclusions Our results demonstrate that HBV facilitates HCC development by activating GP73 to repress the host's innate immune response. This study adds to our understanding of the pathogenesis of HBV infection-induced HCC. The findings also provide preclinical support for GP73 as a potential HCC prevention or treatment target.