Hu Zhibin, Chen Jiaping, Tian Tian, Zhou Xiaoyi, Gu Haiyong, Xu Lin, Zeng Yi, Miao Ruifen, Jin Guangfu, Ma Hongxia, Chen Yijiang, Shen Hongbing
Department of Epidemiology and Biostatistics, Cancer Center of Nanjing Medical University, Nanjing, People's Republic of China.
J Clin Invest. 2008 Jul;118(7):2600-8. doi: 10.1172/JCI34934.
Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non-small cell lung cancer (NSCLC). When we assumed that disease susceptibility was inherited as a recessive phenotype, we found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in individuals with NSCLC. Specifically, survival was significantly decreased in individuals who were homozygous CC at SNP rs11614913. In the genotype-phenotype correlation analysis of 23 human lung cancer tissue samples, rs11614913 CC was associated with a statistically significant increase in mature hsa-mir-196a expression but not with changes in levels of the precursor, suggesting enhanced processing of the pre-miRNA to its mature form. Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.
近期证据表明，被称为微小RNA（miRNA）的小型非编码RNA分子可作为肿瘤抑制因子和癌基因发挥作用。突变、错误表达以及成熟miRNA加工过程的改变与癌症发生和肿瘤进展有关。由于前体miRNA中的单核苷酸多态性（SNP）可能会改变miRNA的加工、表达和/或与靶mRNA的结合，我们对常见的前体miRNA SNP及其周边区域进行了系统调查，并详细评估了其中4个SNP与非小细胞肺癌（NSCLC）患者生存情况的关联。当我们假设疾病易感性作为隐性表型遗传时，发现hsa - mir - 196a2中的rs11614913 SNP与NSCLC患者的生存情况相关。具体而言，在SNP rs11614913处为纯合子CC的个体生存时间显著缩短。在对23个人类肺癌组织样本进行的基因型 - 表型相关性分析中，rs11614913 CC与成熟hsa - mir - 196a表达的统计学显著增加相关，但与前体水平的变化无关，这表明前体miRNA向其成熟形式的加工增强。此外，结合试验表明rs11614913 SNP可影响成熟hsa - mir - 196a2 - 3p与其靶mRNA的结合。因此，hsa - mir - 196a2中的rs11614913 SNP可能是NSCLC的一个预后生物标志物。对miRNA SNP的进一步表征可能为癌症研究和治疗干预开辟新途径。
