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

All Science Journal Classification (ASJC) codes

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

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    Lo, P. H. Y., 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, 8(4), [e61279]. https://doi.org/10.1371/journal.pone.0061279