Hepatitis B virus core protein inhibits Fas-mediated apoptosis of hepatoma cells via regulation of mFas/FasL and sFas expression
Hepatitis B virus core protein inhibits Fas-mediated apoptosis of hepatoma cells via regulation of mFas/FasL and sFas expression
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DOI：
10.1096/fj.14-263822
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发表时间：
2015-03-01
期刊：
影响因子：
4.8
通讯作者：
Lin, Xu
中科院分区：
文献类型：
--
作者：
Liu, Wei;Lin, Yan-Ting;Lin, Xu
乙肝病毒核心蛋白(HBC)通过多种机制参与肝癌的发生。乙肝病毒(乙肝病毒)感染的肝细胞对凋亡的抵抗被认为是慢性肝炎发展为肝硬化并最终发展为肝细胞癌的主要因素之一。Fas受体/配体(Fas/FasL)系统在乙肝病毒感染过程中肝细胞死亡中起重要作用。在此，我们报道了HBC介导的肝癌细胞对激动型抗Fas抗体(CH11)诱导的凋亡的抵抗。当HBc被导入人肝癌细胞后，该细胞对CH11细胞毒产生了依赖于P53的抗性。HBC显著下调P53、总Fas和膜结合Fas在RNA和蛋白水平的表达，并降低FasL基因的表达。相反，HBc通过增加Fas选择性mRNA剪接而上调可溶性Fas的表达。从机制上讲，HBC介导的Fas选择性mRNA剪接与多嘧啶结合蛋白1上调和Fas激活的丝氨酸/苏氨酸激酶下调有关。这些结果表明，HBC可能通过降低促凋亡型Fas的表达和增强抗凋亡型受体的表达来预防Fas诱导的肝细胞凋亡，这可能有助于慢性感染时感染肝细胞的存活和持续。
Hepatitis B virus core protein (HBc) has been implicated in hepatocarcinogenesis through several mechanisms. Resistance of hepatitis B virus (HBV)-infected hepatocytes to apoptosis is considered one of the major contributors to the progression of chronic hepatitis to cirrhosis and ultimately to hepatocellular carcinoma. The Fas receptor/ligand (Fas/FasL) system plays a prominent role in hepatocyte death during HBV infection. Here we report that HBc mediates resistance of hepatoma cells to agonistic anti-Fas antibody (CH11)-induced apoptosis. WhenHBc was introduced into human hepatoma cells, the cells became resistant to CH11 cytotoxicity in a p53-dependent manner. HBc significantly down-regulated the expression of p53, total Fas, and membrane-bound Fas at them RNA and protein levels and reduced FasL mRNA expression. In contrast, HBc upregulated the expression of soluble forms of Fas by increasing Fas alternative mRNA splicing. Mechanistically, HBc-mediated Fas alternative mRNA splicing was associated with up-regulation of polypyrimidine tract-binding protein 1 and down-regulation of Fas-activated serine/threonine kinase. These results indicated that HBc may preventhepatocytes from Fas-induced apoptosis by the dual effects of reducing the expression of the proapoptotic form of Fas and enhancing the expression of the antiapoptotic form of the receptor, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.