title: Identification of a functional variant in the MICA promoter which regulates MICA expression and increases HCV-related hepatocellular carcinoma risk.
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.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Paulisally Hau Yi
authors.initials: PH
authors.lastname: Lo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Urabe
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.forename: Chizu
authors.initials: C
authors.lastname: Tanikawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Naoya
authors.initials: N
authors.lastname: Kato
authors.forename: Daiki
authors.initials: D
authors.lastname: Miki
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D006526:Hepatitis C / Q000150:complications*; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics*; D008156:Luciferases; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D016329:Sp1 Transcription Factor; D008156:Luciferases