Hepatitis B virus deregulates cell cycle to promote viral replication and a premalignant phenotype

Hepatitis B virus (HBV) infection is a major health problem worldwide and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expressions and signaling pathways of infected hepatocytes, and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of transforming growth factor (TGF)- family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 gene associated with cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase as compared to the predominantly G0/G1 phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA and CEBPB, were up-regulated upon HBV infection and particularly enriched in cells at the G2/M phase. Together, these results support that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predispose infected hepatocytes to subsequent malignant transformation.

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Xia Y, Cheng X, Li Y, Valdez K, Chen W, Liang TJ