HBV polymerase overexpression due to large core gene deletion enhances hepatoma cell growth by binding inhibition of microRNA-100
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Ya-Hui Huang1,2, Ying-Hsin Tseng1,2, Wey-Ran Lin1,3, George Hung4, Tse-Ching Chen5, Tong-Hong Wang5, Wei-Chen Lee6, Chau-Ting Yeh1,2
1Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
2Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
3Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
4Department of Molecular Biology, Princeton University, NJ, USA
5Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
6Division of Liver and Transplantation Surgery, Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
Chau-Ting Yeh, e-mail: firstname.lastname@example.org
Keywords: hepatitis B, hepatocellular carcinoma, molecular oncology, mutation screening, microRNA-100
Received: August 03, 2015 Accepted: January 17, 2016 Published: January 25, 2016
Different types of hepatitis B virus (HBV) core gene deletion mutants were identified in chronic hepatitis B patients. However, their clinical roles in different stages of natural chronic HBV infection remained unclear. To address this issue, HBV core genes were sequenced in three gender- and age-matched patient groups diagnosed as chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC), respectively. Functional analysis of the identified mutants was performed. A novel type of large-fragment core gene deletion (LFCD) was identified exclusively in HCC patients and significantly associated with unfavorable postoperative survival. The presence of LFCDs resulted in generation of precore-polymerase fusion protein or brought the polymerase reading frame under direct control of HBV precore/core promoter, leading to its over-expression. Enhanced cell proliferation and increased tumorigenicity in nude mice were found in hepatoma cells expressing LFCDs. Because of the epsilon-binding ability of HBV polymerase, we hypothesized that the over-expressed polymerase carrying aberrant amino-terminal sequence could bind to cellular microRNAs. Screening of a panel of microRNAs revealed physical association of a precore-polymerase fusion protein with microRNA-100. A binding inhibition effect on microRNA-100 by the precore-polymerase fusion protein with up-regulation of its target, polo-like kinase 1 (PLK1), was discovered. The binding inhibition and growth promoting effects could be reversed by overexpressing microRNA-100. Together, HCC patients carrying hepatitis B large-fragment core gene deletion mutants had an unfavorable postoperative prognosis. The growth promoting effect was partly due to polymerase overexpression, leading to binding inhibition of microRNA-100 and up-regulation of PLK1.
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