Hepatitis B virus core protein enhances human telomerase reverse transcriptase expression and hepatocellular carcinoma cell proliferation in a c-Ets2-dependent manner
Hepatitis B virus core protein enhances human telomerase reverse transcriptase expression and hepatocellular carcinoma cell proliferation in a c-Ets2-dependent manner
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乙型肝炎病毒核心蛋白以c-Ets2依赖性方式增强人端粒酶逆转录酶表达和肝癌细胞增殖
DOI：
10.1016/j.biocel.2013.03.015
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Liang, Xiaohong
中科院分区：
文献类型：
--
作者：
Gai, Xiaoxiao;Zhao, Peiqing;Liang, Xiaohong
B型肝炎病毒核心蛋白可调节病毒复制和宿主基因表达。但目前尚不清楚B型肝炎病毒核心蛋白是否以及如何调控肝癌细胞增殖。诱导B型肝炎病毒核心蛋白过表达显著促进肝癌细胞增殖，而敲低B型肝炎病毒核心蛋白表达则抑制肝癌细胞增殖。改变B型肝炎病毒核心蛋白表达可显著改变体内移植性肝癌的生长。基因芯片分析表明，B型肝炎病毒核心蛋白上调人端粒酶逆转录酶的表达，体外过表达和敲低实验进一步验证了这一点。此外，人端粒酶逆转录酶表达的敲低减轻了体外B型肝炎病毒核心蛋白增强的肝癌细胞增殖和克隆形成。荧光素酶检测表明，B型肝炎病毒核心蛋白增强了人端粒酶逆转录酶的启动子活性，这依赖于c-Ets 2与启动子192 - 187之间区域的结合。另外，B型肝炎病毒核心蛋白能增强HepG 2细胞中人端粒酶逆转录酶的转录，但在c-Ets 2沉默的HepG 2细胞中没有增强作用。此外，B型肝炎病毒核心蛋白可促进c-Ets 2核转位。最后，在B型肝炎病毒核心蛋白阳性的肝细胞癌样本中检测到显著更高水平的人端粒酶逆转录酶表达和核c-Ets 2积累。我们的研究结果表明，B型肝炎病毒核心蛋白通过上调c-Ets 2依赖的人端粒酶逆转录酶的表达促进肝癌细胞增殖。(C)2013爱思唯尔有限公司保留所有权利。
Hepatitis B virus core protein can regulate viral replication and host gene expression. However, it is unclear whether and how hepatitis B virus core protein regulates hepatocellular carcinoma cell proliferation. Induction of hepatitis B virus core protein over-expression significantly enhanced the proliferation of hepatocellular carcinoma cells, while knockdown of hepatitis B virus core protein expression inhibited the proliferation of hepatocellular carcinoma cells. Altered hepatitis B virus core protein expression significantly changed the growth of implanted hepatocellular carcinoma in vivo. Microarray analysis indicated that hepatitis B virus core protein up-regulated human telomerase reverse transcriptase expression, which was further validated by over-expression and knockdown assays in vitro. Furthermore, knockdown of human telomerase reverse transcriptase expression mitigated the hepatitis B virus core protein-enhanced hepatocellular carcinoma cell proliferation and clone formation in vitro. Luciferase assays indicated that hepatitis B virus core protein enhanced the promoter activity of human telomerase reverse transcriptase, which was dependent on the binding of c-Ets2 to the promoter region between 192 and -187. In addition, hepatitis B virus core protein enhanced human telomerase reverse transcriptase transcription in HepG2 cells, but not in the c-Ets2-silencing HepG2 cells. Moreover, hepatitis B virus core protein promoted c-Ets2 nuclear translocation. Finally, significantly higher levels of human telomerase reverse transcriptase expression and nuclear c-Ets2 accumulation were detected in hepatitis B virus core protein-positive hepatocellular carcinoma samples. Our findings demonstrate that hepatitis B virus core protein promotes hepatocellular carcinoma cell proliferation by up-regulating the c-Ets2-dependent expression of human telomerase reverse transcriptase. (C) 2013 Elsevier Ltd. All rights reserved.