Hepatitis B virus core protein enhances human telomerase reverse transcriptase expression and hepatocellular carcinoma cell proliferation in a c-Ets2-dependent manner

• Published in: The international journal of biochemistry & cell biology 2013-07, Vol.45 (7), p.1174-1185
• Main Authors: Gai, Xiaoxiao, Zhao, Peiqing, Pan, Yingfang, Shan, Haixia, Yue, Xuetian, Du, Juan, Zhang, Zhenyu, Liu, Peng, Ma, Hongxin, Guo, Min, Yang, Xiaoyun, Sun, Wensheng, Gao, Lifen, Ma, Chunhong, Liang, Xiaohong
• Format: Article
• Language: English
• Subjects: Aged; Animals; Assaying; Biomedical materials; c-Ets2; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation; gene overexpression; HeLa Cells; Hep G2 Cells; Hepatitis B Core Antigens - genetics; Hepatitis B Core Antigens - metabolism; Hepatitis B virus; Hepatitis B virus - genetics; Hepatitis B virus core (HBc); Hepatocellular carcinoma (HCC); hepatoma; Heterografts; Human; human cell lines; Human telomerase reverse transcriptase (hTERT); Humans; in vitro studies; In vitro testing; In vivo testing; Liver Neoplasms; luciferase; Male; Mice; Mice, Inbred BALB C; Mice, Nude; microarray technology; Middle Aged; neoplasm cells; Neoplasm Transplantation; promoter regions; Promoter Regions, Genetic; protein synthesis; Proteins; Proto-Oncogene Protein c-ets-2 - genetics; Proto-Oncogene Protein c-ets-2 - metabolism; RNA Interference; RNA, Small Interfering; Telomerase; Telomerase - biosynthesis; Telomerase - genetics; Transcription activation; Transcriptional Activation; Up-Regulation; virus replication
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2013.03.015

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.