Contribution of C1485T mutation in the HBx gene to human and murine hepatocarcinogenesis

Satoru Hagiwara,Naoshi Nishida,Ah-Mee Park,Tomohiro Watanabe,Yoriaki Komeda,Masatoshi Kudo,Toshiharu Sakurai

doi:10.1038/s41598-017-10570-0

Satoru Hagiwara, Naoshi Nishida + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-10570-0

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Journal: Scientific Reports	Publication Date: Sep 5, 2017
Citations: 4	License type: open-access

Affiliation: Kindai University

Abstract

Although Hepatitis B virus (HBV) X gene mutations are frequently detected in HBV-related human hepatocellular carcinoma (HCC) patients, causative HBx mutations in the development of HCC have not yet been determined. We herein identified C1485T and C1653T mutations in the HBx gene as independent risk of HCC for HBV through the analysis using serum from chronic hepatitis B patients. We generated transgenic mice expressing wild-type (WT-HBxTg) and mutant (C1485T-HBxTg) HBx to assess the carcinogenic potential of mutated HBx. C1485T-HBxTg mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis than WT-HBxTg mice and control non-Tg mice. The promotion of hepatocarcinogenesis in C1485T-HBxTg mice was accompanied by the activation of β-catenin and Jun N-terminal kinase (JNK) signaling pathways as well as the production of reactive oxygen species, whereas the activation of nuclear factor-kappa B in the livers of C1485T-HBxTg mice was attenuated. These results demonstrate that the HBx C1485T mutation contributes to human and murine hepatocarcinogenesis.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and chronic hepatitis B virus (HBV) infection is one of the most important etiologies for the development of HCC1, 2
HBx mutations that lead to the development of Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we initially attempted to identify the sites of mutations in HBx in chronic hepatitis B (CHB) patients with or without HCC
The ratio of liver cirrhosis (LC) and presence of core promoter mutation were significantly higher in patients with HCC than in those without HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and chronic hepatitis B virus (HBV) infection is one of the most important etiologies for the development of HCC1, 2. It is generally accepted that the HBx protein positively and negatively regulates the expression of genes associated with apoptosis, inflammation, and oncogenesis and thereby induces hepatocarcinogenesis[9, 10]. The molecular mechanisms by which the functions of HBx are altered in the presence of HBx mutations and cause the promotion of HBV-related hepatocarcinogenesis have not yet been elucidated in detail. This is the case for HBx C1653T and C1485T mutations associated with the occurrence of HCC in patients with HBV genotype C in Japan[9, 10]. We demonstrated that HBx C1653T and C1485T mutations are associated with the development of HBV-related hepatocarcinogenesis and that the latter mutation induces malignant transformation in hepatocytes upon over-expression

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