A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility.
A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility.
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DOI：
10.1038/emm.2016.50
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发表时间：
2016-07-15
影响因子：
12.8
通讯作者：
Leem SH
中科院分区：
文献类型：
--
作者：
Yoon SL;Roh YG;Chu IS;Heo J;Kim SI;Chang H;Kang TH;Chung JW;Koh SS;Larionov V;Leem SH
BORIS/CTCFL（印迹位点调节器/CTCF样蛋白的兄弟）的异常表达在不同的恶性肿瘤中有报道。在这项研究中，我们的特点是BORIS/CTCFL的整个启动子区，包括CpG岛，评估BORIS表达和肺癌之间的关系。为了简化具有不同大小的上游区域部分的荧光素酶报告盒的构建，使用TAR克隆技术分离BORIS的基因组拷贝。我们分析了三个启动子块：加塔/CCAAT盒，CpG岛和小卫星区BORIS-MS 2。从对照组和病例组血液中制备的基因组DNA中分离出多态性小卫星序列。在三个启动子块中，加塔/CCAAT盒被确定为核心启动子的关键元件，而CpG岛和BORIS-MS 2小卫星区域被发现起调节器的作用。有趣的是，多态性小卫星区域BORIS-MS 2被鉴定为负调节剂，与正常细胞相比，其在癌细胞中较不有效地抑制荧光素酶报告盒的表达水平。我们还在一项病例对照研究中研究了BORIS-MS 2大小与肺癌之间的关系，该研究包括590例对照和206例肺癌病例。BORIS-MS 2的罕见等位基因与肺癌风险的统计学显著增加相关（比值比，2.04; 95%置信区间，1.02-4.08; P=0.039）。总之，我们的数据提供了关于BORIS启动子区域的组织和正常细胞和癌细胞中的基因调控的信息。此外，我们提出BORIS-MS 2区域的特定等位基因可用于识别肺癌的风险。
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.