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MICA SNPs and the NKG2D system in virus-induced HCC

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Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death globally. Above well-known risk factors for HCC development ranging from various toxins to diseases such as diabetes mellitus, chronic infection with hepatitis B virus and hepatitis C virus (HCV) poses the most serious threat, constituting the cause in more than 80 % of cases. In addition to the viral genes intensively investigated, the pathophysiological importance of host genetic factors has also been greatly and increasingly appreciated. Genome-wide association studies (GWAS) comprehensively search the host genome at the single-nucleotide level, and have successfully identified the genomic region associated with a whole variety of diseases. With respect to HCC, there have been reports from several groups on single nucleotide polymorphisms (SNPs) associated with hepatocarcinogenesis, among which was our GWAS discovering MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for HCV-induced HCC. MICA is a natural killer (NK) group 2D (NKG2D) ligand, whose interaction with NKG2D triggers NK cell-mediated cytotoxicity toward the target cells, and is a key molecule in tumor immune surveillance as its expression is induced on stressed cells such as transformed tumor cells for the detection by NK cells. In this review, the latest understanding of the MICA–NKG2D system in viral HCC, particularly focused on its antitumor properties and the involvement of MICA SNPs, is summarized, followed by a discussion of targets for state-of-the-art cancer immunotherapy with personalized medicine in view.

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Abbreviations

ADAM:

A disintegrin and metalloprotease

ATM:

Ataxia–telangiectasia mutated

CHB:

Chronic hepatitis B

CHC:

Chronic hepatitis C

DAP10:

DNAX-activating protein of 10 kDa

GWAS:

Genome-wide association study

HBV:

Hepatitis B virus

HBx:

Hepatitis B virus encoded X protein

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HDAC:

Histone deacetylase

IFN:

Interferon

Met:

Methionine

MIC:

MHC class I chain

MICA:

MHC class I polypeptide-related sequence A

MICA-129:

Amino acid 129 of MHC class I polypeptide-related sequence A

miRNA:

MicroRNA

mMICA:

Membrane-bound MHC class I polypeptide-related sequence A

MMP:

Matrix metalloproteinase

NKG2D:

Natural killer group 2D

NKG2DL:

Natural killer group 2D ligand

sMICA:

Soluble MHC class I polypeptide-related sequence A

SNP:

Single nucleotide polymorphism

TGF-β:

Transforming growth factor β

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

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Acknowledgments

N.K. is supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan. K.G. is a recipient of Research Fellowships of the Japan Society for the Promotion of Science (JSPS) for Young Scientists. The authors appreciate critical reading of the manuscript and comments by Dr. Masahisa Jinushi, Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Hokkaido, Japan.

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The authors disclose no conflict of interest.

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  1. Division of Advanced Genome Medicine, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan

    Kaku Goto & Naoya Kato

  2. Japan Society for the Promotion of Science, Tokyo, 102-8472, Japan

    Kaku Goto

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  1. Kaku Goto
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  2. Naoya Kato
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Correspondence to Naoya Kato.

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Goto, K., Kato, N. MICA SNPs and the NKG2D system in virus-induced HCC. J Gastroenterol 50, 261–272 (2015). https://doi.org/10.1007/s00535-014-1000-9

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