Feng Guoxing, Li Jiong, Zheng Minying, Yang Zhe, Liu Yunxia, Zhang Shuqin, Ye Lihong, Zhang Weiying, Zhang Xiaodong
State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, P.R. China.
State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China.
Oncotarget. 2016 May 10;7(19):28013-26. doi: 10.18632/oncotarget.8472.
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 α (C4BPα), a potent inhibitor of complement system. We observed that HBx were positively correlated with those of C4BPα in clinical HCC tissues. Mechanistically, HBx activated the promoter core region of C4BPα, 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 C4BPα, which could be blocked by Sp1 silencing. Functionally, knockdown of C4BPα 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 C4BPα 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.
乙型肝炎病毒X蛋白（HBx）在肝细胞癌（HCC）的发生发展中起着关键作用。我们之前表明，HBx通过激活CD59保护肝癌细胞免受补体攻击。此外，在本研究中我们发现，HBx通过激活补体系统的强效抑制剂C4b结合蛋白α（C4BPα）保护肝癌细胞免受补体攻击。我们观察到在临床肝癌组织中HBx与C4BPα呈正相关。机制上，HBx通过与转录因子Sp1结合激活位于-1199/-803nt的C4BPα启动子核心区域。此外，染色质免疫沉淀（ChIP）分析表明HBx能够结合C4BPα的启动子，而这可被Sp1沉默所阻断。功能上，敲低C4BPα明显增加了补体膜攻击复合物C5b-9的沉积，并显著消除了HBx在体外和体内诱导的肝癌细胞对补体攻击的抗性。因此，我们得出结论，HBx通过激活转录因子Sp1上调C4BPα，从而保护肝癌细胞免受补体攻击。我们的发现为HBx增强肝癌细胞对补体攻击的保护机制提供了新的见解。
