Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk

Paulisally Hau Yi Lo, Yuji Urabe, Vinod Kumar, Chizu Tanikawa, Kazuhiko Koike, Naoya Kato, Daiki Miki, Kazuaki Chayama, Michiaki Kubo, Yusuke Nakamura, Koichi Matsuda

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Abstract

Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10-5 and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.

Original languageEnglish
Article numbere61279
JournalPloS one
Volume8
Issue number4
DOIs
Publication statusPublished - 11-04-2013

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Hepatitis C virus
hepatoma
Viruses
Hepacivirus
Single Nucleotide Polymorphism
Hepatocellular Carcinoma
promoter regions
alleles
Alleles
Assays
Genes
Association reactions
Sp1 Transcription Factor
Electrophoretic mobility
Functional analysis
5' Flanking Region
Nuclear Proteins
Genetic Promoter Regions
nuclear proteins
Chromatin

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lo, Paulisally Hau Yi ; Urabe, Yuji ; Kumar, Vinod ; Tanikawa, Chizu ; Koike, Kazuhiko ; Kato, Naoya ; Miki, Daiki ; Chayama, Kazuaki ; Kubo, Michiaki ; Nakamura, Yusuke ; Matsuda, Koichi. / Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk. In: PloS one. 2013 ; Vol. 8, No. 4.
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abstract = "Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10-5 and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.",
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Lo, PHY, Urabe, Y, Kumar, V, Tanikawa, C, Koike, K, Kato, N, Miki, D, Chayama, K, Kubo, M, Nakamura, Y & Matsuda, K 2013, 'Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk', PloS one, vol. 8, no. 4, e61279. https://doi.org/10.1371/journal.pone.0061279

Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk. / Lo, Paulisally Hau Yi; Urabe, Yuji; Kumar, Vinod; Tanikawa, Chizu; Koike, Kazuhiko; Kato, Naoya; Miki, Daiki; Chayama, Kazuaki; Kubo, Michiaki; Nakamura, Yusuke; Matsuda, Koichi.

In: PloS one, Vol. 8, No. 4, e61279, 11.04.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk

AU - Lo, Paulisally Hau Yi

AU - Urabe, Yuji

AU - Kumar, Vinod

AU - Tanikawa, Chizu

AU - Koike, Kazuhiko

AU - Kato, Naoya

AU - Miki, Daiki

AU - Chayama, Kazuaki

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

AU - Matsuda, Koichi

PY - 2013/4/11

Y1 - 2013/4/11

N2 - Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10-5 and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.

AB - Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10-5 and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.

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