Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biochem Biophys Res Commun. 2013 Jan 11;430(2):529-34. doi: 10.1016/j.bbrc.2012.12.001. Epub 2012 Dec 8.
Polymorphisms in 3' untranslated region (UTR) of cancer-related genes might affect their regulation by microRNAs (miRNAs) and thereby contribute to carcinogenesis. In this study, we screened single nucleotide polymorphisms (SNPs) in 3' UTR of cancer-related genes and investigated their effects on risk of lung cancer. First, we genotyped seven SNPs in a Chinese Han population with 600 lung cancer patients and 600 matched healthy controls and found that compared with the TT genotype of rs2239680 in 3' UTR of baculoviral IAP repeat containing 5 (BIRC5), C allele was associated with a significantly increased risk of lung cancer and advanced pathologic stage, with the odds ratio for participants carrying the CT or CC genotype being 1.50 [95% confidence interval (CI) 1.20-1.89, P<0.01] and 2.29 (95% CI 1.64-3.18, P<0.01), respectively. These results were further replicated and confirmed in another independent population with 1000 lung cancer cases and 1000 matched healthy controls. In support of the postulation that the 3' UTR SNP may directly affect miRNA-binding site, reporter gene assays indicated BIRC5 was a direct target of miR-335, and the rs2239680 T>C change resulted in altered regulation of BIRC5 expression. Moreover, BIRC5 was over expressed in lung cancer tissues compared with the normal lung tissues, and the protein levels of BIRC5 correlated with SNP genotypes in normal lung tissues. Our findings defined a 3' UTR SNP in human BIRC5 oncogene that may increase individual susceptibility to lung cancer probably by attenuating the interaction between miR-335 and BIRC5.
癌症相关基因 3' 非翻译区（UTR）的多态性可能影响 microRNAs（miRNAs）对其的调控，从而促进肿瘤的发生。在这项研究中，我们筛选了癌症相关基因 3'UTR 的单核苷酸多态性（SNP），并研究了它们对肺癌风险的影响。首先，我们在一个包含 600 例肺癌患者和 600 例匹配健康对照的中国汉族人群中对 7 个 SNP 进行了基因分型，发现与 baculoviral IAP repeat containing 5（BIRC5）3'UTR 中的 rs2239680 的 TT 基因型相比，C 等位基因与肺癌和晚期病理分期的风险显著增加相关，携带 CT 或 CC 基因型的参与者的比值比为 1.50[95%置信区间（CI）1.20-1.89，P<0.01]和 2.29（95%CI 1.64-3.18，P<0.01）。这些结果在另一个包含 1000 例肺癌病例和 1000 例匹配健康对照的独立人群中得到了进一步复制和证实。支持 3'UTR SNP 可能直接影响 miRNA 结合位点的假设，报告基因检测表明 BIRC5 是 miR-335 的直接靶标，rs2239680 T>C 变化导致 BIRC5 表达的调节改变。此外，与正常肺组织相比，BIRC5 在肺癌组织中过度表达，并且 BIRC5 的蛋白水平与正常肺组织中的 SNP 基因型相关。我们的研究结果确定了人类 BIRC5 癌基因中的一个 3'UTR SNP，它可能通过减弱 miR-335 和 BIRC5 之间的相互作用来增加个体患肺癌的易感性。
