title: A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility.
abstract: Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case-control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02-4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer.
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Se-Lyun
authors.initials: SL
authors.lastname: Yoon
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Yun-Gil
authors.initials: YG
authors.lastname: Roh
authors.affiliation: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Chu
authors.affiliation: Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Korea.
authors.forename: Jeonghoon
authors.initials: J
authors.lastname: Heo
authors.affiliation: Drug & Disease Target Team, Korea Basic Science Institute, Daejeon, Korea.
authors.forename: Seung Il
authors.initials: SI
authors.lastname: Kim
authors.affiliation: Department of Pathology, Kosin University College of Medicine, Busan, Korea.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chang
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Tae-Hong
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Jin Woong
authors.initials: JW
authors.lastname: Chung
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.affiliation: Developmental Therapeutic Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Larionov
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Leem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002460:Cell Line; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: C456540:CTCFL protein, human; D004268:DNA-Binding Proteins