Pathogenesis of hepatitis B virus infection: The effect of the HBx protein from HBV on cell survival and death.

摘要

Human hepatitis B virus (HBV) is one of several agents causing infectious hepatitis, which can lead to the development of liver cirrhosis and hepatocellular carcinoma (HCC). HBV-related HCC is among the top 10 most frequent cancers throughout the world. More than 400 million people worldwide are chronically infected with this virus. Currently, no effective treatment is available for those with established HBV infections, despite the recent development of a recombinant vaccine for protecting previously unexposed individuals. The exact molecular events involved in HBV-related liver carcinogenesis remain to be elucidated. A viral protein, the HBx protein from HBV has been implicated in the liver carcinogenesis after HBV infection. The work presented in this thesis explores the mechanism of HBx's involvement in liver cancer, focusing on its effect on apoptosis and its interaction with cellular signaling pathways. Experiments demonstrated that cell apoptosis caused by anti-Fas antibodies and serum deprivation can be blocked by the expression of the HBx protein. However, fibroblasts that are SEK1 deficient still undergo Fas-mediated apoptosis whether or not the viral protein is present. Under low serum condition, cells treated with PI3-K inhibitor lose the survival advantage provided by the HBx protein. Therefore, it is suggested that interactions with SEK1-dependent pathway and PI3K-dependent pathway are responsible for the effect of the HBx protein on Fas-mediated apoptosis and serum-starvation-mediated apoptosis, respectively. Experiments further demonstrated that the HBx protein interacts with SEK1-dependent SAPK and PI3K-PKB signaling pathway and enhances the SAPK and PKB activities, which contribute to the protective effects of the HBx protein on cells under specific apoptotic stimuli. Lastly, interaction of the HBx protein with the components in the apoptotic pathway was also studied. Results show that the HBx protein targets the apoptotic pathway, perhaps mainly by locating on the mitochondria and cooperating with an anti-apoptotic molecule Bcl-X_L. Generally, data presented in this thesis indicates that the HBx protein can be involved in the multiple regulatory steps in survival and death signaling. HBx protein is thus suggested to be a multifunctional viral regulator strongly implicated in hepatocarcinogenesis.