title: Hepatitis B virus core protein enhances human telomerase reverse transcriptase expression and hepatocellular carcinoma cell proliferation in a c-Ets2-dependent manner.
abstract: 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.
authors.affiliation: Key Laboratory for Experimental Teratology of Ministry of Education and Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Gai
authors.forename: Peiqing
authors.initials: P
authors.lastname: Zhao
authors.forename: Yingfang
authors.initials: Y
authors.lastname: Pan
authors.forename: Haixia
authors.initials: H
authors.lastname: Shan
authors.forename: Xuetian
authors.initials: X
authors.lastname: Yue
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Hongxin
authors.initials: H
authors.lastname: Ma
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Yang
authors.forename: Wensheng
authors.initials: W
authors.lastname: Sun
authors.forename: Lifen
authors.initials: L
authors.lastname: Gao
authors.forename: Chunhong
authors.initials: C
authors.lastname: Ma
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liang
mesh_terms: D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056945:Hep G2 Cells; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C494069:ETS2 protein, human; D006512:Hepatitis B Core Antigens; D050787:Proto-Oncogene Protein c-ets-2; D034741:RNA, Small Interfering; D019098:Telomerase