Hepatitis B Virus X Protein Up-Regulates C4b-binding Protein Α Through Activating Transcription Factor Sp1 in Protection of Hepatoma Cells from Complement Attack.

Hepatitis B virus X protein (HBx) plays crucial roles in the development of hepatocellular carcinoma (HCC). We previously showed that HBx protected hepatoma cells from complement attack by activation of CD59. Moreover, in this study we found that HBx protected hepatoma cells from complement attack by activation of C4b-binding protein beta (C4BP beta), a potent inhibitor of complement system. We observed that HBx were positively correlated with those of C4BP beta in clinical HCC tissues. Mechanistically, HBx activated the promoter core region of C4BP beta, located at -1199/-803nt, through binding to transcription factor Sp1. In addition, chromatin immunoprecipitation (ChIP) assays showed that HBx was able to bind to the promoter of C4BP beta, which could be blocked by Sp1 silencing. Functionally, knockdown of C4BP beta obviously increased the deposition of C5b-9, a complex of complement membrane attack, and remarkably abolished the HBx-induced resistance of hepatoma cells from complement attack in vitro and in vivo. Thus, we conclude that HBx up-regulates C4BP beta through activating transcription factor Sp1 in protection of liver cancer cells from complement attack. Our finding provides new insights into the mechanism by which HBx enhances protection of hepatoma cells from complement attack.