Journal Article

Identification of Transforming Hepatitis B Virus S Gene Nonsense Mutations Derived from Freely Replicative Viruses in Hepatocellular Carcinoma

Lai, Ming-Wei, Matsuura, Isao, Lee, Wei-Chen, Yuh, Chiou-Hwa, Chang, Il-Chi, Chiu, Yu-Ting, Chen, Ya-Ting, Tu, Hsiao-Chen, Yeh, Chau-Ting, Wu, Hong-Dar Isaac, Chang, Yu, Shih, Liang-Yu, Huang, Shiu-Feng, Chen, Miin-Fu

2014

Overview

The correlation between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) has been well-established. But the roles of viral factor remain uncertain. Only HBV X gene and nonsense mutations of S gene (C-terminal truncation of HBV surface protein) have been demonstrated to have transforming activity. Whether they play a significant role in hepatocarcinogenesis is still uncertain. Twenty-five HBV-related HCC patients were positive for hepatitis B core antigen (HBcAg) in the cancerous parts of their HCC liver tissues by immunohistochemistry studies, and had available tissue for whole HBV genome sequence analysis. The results were compared with 25 gender and age-matched HBcAg negative HCCs. Plasmids encoding HBV S gene nonsense mutations identified from HBcAg (+) HCC tissue were constructed to investigate their cell proliferation, transformation activity and the oncogenic potentials by xenograft study and in vivo migration assay. HBcAg (+) HCC patients were significantly associated with cirrhosis and small tumor size (≦2 cm) when compared with HBcAg (-) HCC patients. Southern blot analyses revealed freely replicative forms of HBV in the cancerous parts of HBcAg(+) HCC. Three nonsense mutations of S gene (sL95*, sW182*, and sL216*) were identified in the HBcAg(+) HCC tumor tissues. sW182* and sL216* were recurrently found in the 25 HBcAg (-) HCC tumor tissue, too. Functional studies of the above 3 non-sense mutations all demonstrated higher cell proliferation activities and transformation abilities than wild type S, especially sW182*. Tumorigenicity analysis by xenograft experiments and in vitro migration assay showed potent oncogenic activity of sW182* mutant. This study has demonstrated potent oncogenic activity of nonsense mutations of HBV S gene, suggesting they may play an important role in hepatocarcinogenesis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Antigens / Biology / Blotting, Southern / Cancer genetics / Carcinoma, Hepatocellular - complications / Carcinoma, Hepatocellular - pathology / Carcinoma, Hepatocellular - virology / Cell proliferation / Cell Transformation, Neoplastic - genetics / Chronic infection / Cirrhosis / Codon, Nonsense - genetics / Core protein / Deoxyribonucleic acid / DNA / Endoplasmic Reticulum - metabolism / Genes / Genetic aspects / Genetic transformation / Genomes / Genomics / Health aspects / Hepatitis / Hepatitis B / Hepatitis B - complications / Hepatitis B core antigen / Hepatitis B virus / Hepatitis B virus - genetics / Hepatitis B virus - metabolism / Hepatocellular carcinoma / Hepatology / Hospitals / Humans / Immunohistochemistry / In vivo methods and tests / Infection / Infections / Liver / Liver cancer / Liver cirrhosis / Liver Neoplasms - complications / Liver Neoplasms - pathology / Liver Neoplasms - virology / Medical research / Medicine / Mutation / Nucleotide sequence / Pathology / Patients / Plasmids / Plasmids - genetics / Proteins / S gene / Sequence Analysis, DNA / Studies / Tissues / Transformation / Tumorigenicity / Viral Fusion Proteins - genetics / Viruses / Xenografts