The X protein of hepatitis B virus inhibits apoptosis in hepatoma cells through enhancing the methionine adenosyltransferase 2A gene expression and reducing S-adenosylmethionine production.
The X protein of hepatitis B virus inhibits apoptosis in hepatoma cells through enhancing the methionine adenosyltransferase 2A gene expression and reducing S-adenosylmethionine production.
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乙型肝炎病毒X蛋白通过增强甲硫氨酸腺苷转移酶2A基因表达并减少S-腺苷甲硫氨酸产生抑制肝癌细胞凋亡
DOI：
10.1074/jbc.m110.167783
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发表时间：
2011-05-13
期刊：
影响因子：
--
通讯作者：
Wu J
中科院分区：
文献类型：
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作者：
Liu Q;Chen J;Liu L;Zhang J;Wang D;Ma L;He Y;Liu Y;Liu Z;Wu J
B型肝炎病毒（HBV）的X蛋白（HBx）参与了肝细胞癌（HCC）的发生发展，而甲硫氨酸腺苷转移酶2A（MAT 2A）通过改变S-腺苷甲硫氨酸稳态促进肝癌细胞的生长。因此，我们推测HBx和MAT 2A之间的联系可能有助于HCC的发展。在这项研究中，HBx对MAT 2A表达和细胞凋亡的影响进行了研究，并评估了HBx和MAT 2A调节肿瘤发生的分子机制。37对HBV相关肝癌组织/相应癌旁组织的免疫组化分析结果显示，HBx和MAT 2A在大多数肝肿瘤组织中高表达。我们的体外研究结果表明，HBx以剂量依赖的方式激活肝癌细胞中的MAT 2A表达，并且这种调节需要MAT 2A基因启动子上的顺式调节元件NF-κB和CREB。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）进一步证实HBx促进NF-κB和CREB与MAT 2A基因启动子的结合。此外，HBx或MAT 2A的过表达抑制细胞凋亡，而MAT 2A表达的敲低刺激肝癌细胞的凋亡。此外，我们证明了HBx降低了MAT 1A表达和β Met产生，但增强了MAT 2 β表达。因此，我们认为HBx通过NF-κB和CREB信号通路激活MAT 2A的表达，从而减少肝癌细胞中MAT的产生，抑制肝癌细胞凋亡，并可能促进肝癌的发展。这些发现将为我们理解HBV感染对MAT 2A产生和HCC发展的影响的分子机制提供新的见解。
The X protein (HBx) of hepatitis B virus (HBV) is involved in the development of hepatocellular carcinoma (HCC), and methionine adenosyltransferase 2A (MAT2A) promotes the growth of liver cancer cells through altering S-adenosylmethionine homeostasis. Thus, we speculated that a link between HBx and MAT2A may contribute to HCC development. In this study, the effects of HBx on MAT2A expression and cell apoptosis were investigated, and the molecular mechanism by which HBx and MAT2A regulate tumorigenesis was evaluated. Results from immunohistochemistry analyses of 37 pairs of HBV-associated liver cancer tissues/corresponding peritumor tissues showed that HBx and MAT2A are highly expressed in most liver tumor tissues. Our in vitro results revealed that HBx activates MAT2A expression in a dose-dependent manner in hepatoma cells, and such regulation requires the cis-regulatory elements NF-κB and CREB on the MAT2A gene promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) further demonstrated that HBx facilitates the binding of NF-κB and CREB to MAT2A gene promoter. In addition, overexpression of HBx or MAT2A inhibits cell apoptosis, whereas knockdown of MAT2A expression stimulates apoptosis in hepatoma cells. Furthermore, we demonstrated that HBx reduces MAT1A expression and AdoMet production but enhances MAT2β expression. Thus, we proposed that HBx activates MAT2A expression through NF-κB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. These findings should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC.