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Gastroenterology. 2014 Feb;146(2):562-72. doi: 10.1053/j.gastro.2013.10.056. Epub 2013 Oct 30.

Hepatitis virus infection affects DNA methylation in mice with humanized livers.

Author information

1
Division of Epigenomics, Aichi Cancer Center, Nagoya, Japan; Division of Molecular Oncology, Aichi Cancer Center, Nagoya, Japan; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medicine, Nagoya, Japan.
2
Division of Epigenomics, Aichi Cancer Center, Nagoya, Japan; Division of Oncological Pathology, Aichi Cancer Center, Nagoya, Japan.
3
Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan.
4
Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan.
5
Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
6
Division of Molecular Oncology, Aichi Cancer Center, Nagoya, Japan.
7
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
8
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medicine, Nagoya, Japan.
9
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
10
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
11
Cancer Epigenetics Program, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.
12
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania.
13
Division of Epigenomics, Aichi Cancer Center, Nagoya, Japan; Division of Molecular Oncology, Aichi Cancer Center, Nagoya, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan. Electronic address: ykondo@aichi-cc.jp.

Abstract

BACKGROUND & AIMS:

Cells of tumors associated with chronic inflammation frequently have altered patterns of DNA methylation, including hepatocellular carcinomas. Chronic hepatitis has also been associated with aberrant DNA methylation, but little is known about their relationship.

METHODS:

Pyrosequencing was used to determine the methylation status of cultured Huh7.5.1 hepatoma cells after hepatitis C virus (HCV) infection. We also studied mice with severe combined immunodeficiency carrying the urokinase-type plasminogen activator transgene controlled by an albumin promoter (urokinase-type plasminogen activator/severe combined immunodeficient mice), in which up to 85% of hepatocytes were replaced by human hepatocytes (chimeric mice). Mice were given intravenous injections of hepatitis B virus (HBV) or HCV, liver tissues were collected, and DNA methylation profiles were determined at different time points after infection. We also compared methylation patterns between paired samples of hepatocellular carcinomas and adjacent nontumor liver tissues from patients.

RESULTS:

No reproducible changes in DNA methylation were observed after infection of Huh7.5.1 cells with HCV. Livers from HBV- and HCV-infected mice had genome-wide, time-dependent changes in DNA methylation, compared with uninfected urokinase-type plasminogen activator/severe combined immunodeficient mice. There were changes in 160 ± 63 genes in HBV-infected and 237 ± 110 genes in HCV-infected mice. Methylation of 149 common genes increased in HBV- and HCV-infected mice; methylation of some of these genes also increased in hepatocellular carcinoma samples from patients compared with nontumor tissues. Expression of Ifng, which is expressed by natural killer cells, increased significantly in chimeric livers, in concordance with induction of DNA methylation, after infection with HBV or HCV. Induction of Ifng was reduced after administration of an inhibitor of natural killer cell function (anti-asialo GM1).

CONCLUSIONS:

In chimeric mice with humanized livers, infection with HBV and HCV appears to activate a natural kill cell-dependent innate immune response. This contributes to the induction and accumulation of aberrant DNA methylation in human hepatocytes.

KEYWORDS:

ESR1; Epigenetic; Gene Regulation; HBV; HBx; HCC; HCV; HOXA6; IFN; Inflammatory Response; Liver Cancer; MCAM; NK; PCNA; RASSF1A; ROS; Ras association domain family 1 isoform A; SCID; estrogen receptor 1; hepatitis B virus; hepatitis B virus X; hepatitis C virus; hepatocellular carcinoma; homeobox A6; interferon; methylated CpG island amplification microarray; natural killer; proliferating cell nuclear antigen; reactive oxygen species; severe combined immunodeficient

PMID:
24184133
DOI:
10.1053/j.gastro.2013.10.056
[Indexed for MEDLINE]

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