A functional polymorphism at microRNA-629-binding site in the 3′-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population
A functional polymorphism at microRNA-629-binding site in the 3′-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population
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DOI：
10.1093/carcin/bgr272
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发表时间：
2012-02-01
期刊：
影响因子：
4.7
通讯作者：
Lu, Jiachun
中科院分区：
文献类型：
--
作者：
Yang, Lei;Li, Yinyan;Lu, Jiachun
据报道，NBS1 基因的遗传变异与癌症风险相关。 NBS1 3'-非翻译区 (3'-UTR) 的多态性可能影响基因的功能，从而导致癌症易感性。我们假设 NBS1 的这些多态性与肺癌风险相关。在华南和华东地区进行的两项独立病例对照研究中，我们对华南地区的三个 tagSNP（rs14448、rs13312986 和 rs2735383）进行了基因分型，然后在华东地区验证了所发现的关联。 rs13312986 和 rs14448 没有观察到显着关联；我们仅发现，与 GG 或 GC 基因型相比，在隐性遗传模型下，与 1679 例对照相比，rs2735383CC 基因型在隐性遗传模型下患肺癌的风险显着增加（比值比 = 1.40，95% 置信区间 = 1.18-1.66，P = 0.0001）；定量聚合酶链反应和蛋白质印迹显示，rs2735383CC基因型携带者在肿瘤组织中的信使RNA和蛋白质表达水平低于其他基因型。荧光素酶检测显示rs2735383C等位基因的转录活性低于G等位基因，并且hsa-miR-629而非hsa-miR-499-5P在体外对NBS1基因的调节有影响。我们进一步观察到，与其他基因型受试者相比，X 射线辐射在 rs2735383CC 纯合子携带者的淋巴细胞中诱导更多的染色单体断裂（P = 0.0008）。我们的数据表明，rs2735383G>C 变异通过将 microRNA-629 与 NBS1 基因 3'-UTR 中的多态性位点结合来减少基因表达，从而导致肺癌风险增加。
The genetic variations in NBS1 gene have been reported to be associated with cancer risk. The polymorphisms in 3'-untranslated region (3'-UTR) of NBS1 might affect gene's function and thus contribute to cancer susceptibility. We hypothesized that these polymorphisms of NBS1 are associated with the lung cancer risk. In two independent case-control studies conducted in Southern and Eastern Chinese, we genotyped three tagSNPs (rs14448, rs13312986 and rs2735383) in Southern Chinese and then validated the discovered association in Eastern Chinese. No significant association was observed for rs13312986 and rs14448; we only found that the rs2735383CC genotype had a significantly increased risk of lung cancer under a recessive genetic model in the total 1559 cases versus 1679 controls (odds ratio = 1.40, 95% confidence interval = 1.18-1.66, P = 0.0001) when compared with GG or GC genotypes; the rs2735383CC genotype carriers had lower messenger RNA and protein expression levels in tumor tissues than those of other genotypes as quantitative polymerase chain reaction and western blot shown. Luciferase assay revealed that the rs2735383C allele had a lower transcription activity than G allele, and the hsa-miR-629 but not hsa-miR-499-5P had effect on modulation of NBS1 gene in vitro. We further observed that the X-ray radiation induced more chromatid breaks in lymphocyte cells from the carriers of rs2735383CC homozygote than those from the subjects with other genotypes (P = 0.0008). Our data suggested that the rs2735383G>C variation contributes to an increased risk of lung cancer by diminishing gene's expression through binding of microRNA-629 to the polymorphic site in the 3'-UTR of NBS1 gene.