Abstract
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.
Highlights
Over 350 million people worldwide suffer from chronic hepatitis B virus (HBV) infection, resulting in about one million deaths per year due to acute liver failure, decompensated liver cirrhosis, and hepatocellular carcinoma (HCC) [1]
Because the large-fragment core gene deletion (LFCD) was detected exclusively in HCC patients, we investigated its roles in hepatoma cell growth
By analyzing HBV core gene sequences in the HBV-infected patient groups, we identified two short core internal deletion (CID) (< 120 nt.) in the cirrhotic patients (2/33, 6.06%) and a novel core gene deletion (LFCD, > 450 nt.) in HCC patients (5/33, 15.1%)
Summary
Over 350 million people worldwide suffer from chronic hepatitis B virus (HBV) infection, resulting in about one million deaths per year due to acute liver failure, decompensated liver cirrhosis, and hepatocellular carcinoma (HCC) [1]. During acute and chronic infection, genomic mutations develop in HBV viral sequences Several of these mutations have been extensively studied, including precore-stop-codon, pre-S deletion, X truncation and basal core promoter (BCP) mutations. Distinct types of naturally occurring HBV core gene deletion mutants have been reported in patients with www.impactjournals.com/oncotarget chronic HBV infection [2,3,4,5,6,7,8,9]. Persistence of such mutants may contribute to the chronicity of diseases [2]. The prevalence and clinical roles of core gene deletions in different stages of chronic HBV infected adults have never been carefully investigated
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