Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer
Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer
复制标题
DOI：
10.1093/carcin/bgm304
复制
发表时间：
2008-03-01
期刊：
影响因子：
4.7
通讯作者：
Landi, Stefano
中科院分区：
文献类型：
--
作者：
Landi, Debora;Gemignani, Federica;Landi, Stefano
最近的证据表明，被称为microRNAs(MiRNAs)的非编码小RNA分子可以与信使RNAs的3‘非翻译区(UTRs)结合并干扰其翻译，从而调控细胞的生长、分化、凋亡和肿瘤发生。遗传多态可能存在于miRNA结合位点。因此，可以想象miRNA的调节可能受到3‘UTRs上的多态性的影响。由于基因失控是细胞发展为癌症的关键机制之一，我们假设miRNA靶标结合位点中常见的多态可能在个体癌症风险中发挥作用。在本研究中，我们选择了104个结直肠癌候选基因的3‘UTRs，并通过专门的算法(PicTar、DianaMicroT、miRBase、Miranda、TargetScan和microInspector)确定了可能的miRNA结合位点。在miRNA结合位点检测到57个单核苷酸多态(SNPs)。我们通过评估每个SNP的两个等位基因之间的Gibbs自由能差异，评估了SNP影响miRNA与其靶标结合的能力。我们发现了8个常见的多态性，并通过病例对照关联研究进行了进一步的研究。这项研究是在捷克共和国的一系列病例和对照上进行的，捷克共和国是世界上CRC发病率最高的人口。我们发现CD86变异等位基因[优势比(OR)=2.74；95%可信区间(CI)=1.24~6.04]和INSR基因(OR=1.94；95%CI=1.03~3.66)与结直肠癌的发病风险显著相关。这些结果首次报道了miRNA结合SNPs序列与癌症风险之间的正相关关系。
Recent evidence indicate that small non-coding RNA molecules, called micro-RNAs (miRNAs), can bind to the 3' untranslated regions (UTRs) of messenger RNAs and interfere with their translation, thereby regulating cell growth, differentiation, apoptosis and tumorigenesis. Genetic polymorphisms can reside on miRNA-binding sites. Thus, it is conceivable that the miRNA regulation may be affected by polymorphisms on the 3' UTRs. Since gene deregulation is one of the key mechanisms by which cells can progress to cancer, we hypothesize that common polymorphisms within miRNA-target binding sites could play a role in the individual risk of cancer. In the present study, we selected the 3' UTRs of 104 genes candidate for colorectal cancer (CRC) and we identified putative miRNA-binding sites by specialized algorithms (PicTar, DianaMicroT, miRBase, miRanda, TargetScan and microInspector). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified in miRNA-binding sites. We evaluated the SNPs for their ability to affect the binding of the miRNA with its target, by assessing the variation of Gibbs free energy between the two alleles of each SNP. We found eight common polymorphisms that were further investigated by a case-control association studies. The study was carried out on a series of cases and controls from Czech Republic, a population with the highest worldwide incidence of CRC. We found statistically significant associations between risk of CRC and variant alleles of CD86 [odds ratio (OR) = 2.74; 95% confidence interval (CI) = 1.24-6.04, for the variant homozygotes] and INSR genes (OR = 1.94; 95% CI = 1.03-3.66, for the variant homozygotes). These results are the first reporting positive association between miRNA-binding SNPs sequences and cancer risk.