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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• 作者：Xiaoxiao Gai^a ; ¹ ; Peiqing Zhao^a ; ^b ; ¹ ; Yingfang Pan^a ; Haixia Shan^a ; Xuetian Yue^a ; Juan Du^c ; Zhenyu Zhang^a ; Peng Liu^a ; Hongxin Ma^a ; Min Guo^a ; Xiaoyun Yang^d ; Wensheng Sun^a ; Lifen Gao^a ; Chunhong Ma^a ; Xiaohong Liang^a ; ^{liangxiaohong@sdu.edu.cn}
• 关键词：Hepatitis B virus core (HBc) ; Hepatocellular carcinoma (HCC) ; Human telomerase reverse transcriptase (hTERT) ; Transcription activation ; c-Ets2
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：45
• 期：7
• 页码：1174-1185
• 全文大小：2916 K

文摘

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.