A functional polymorphism in lnc-LAMC2-1:1 confers risk of colorectal cancer by affecting miRNA binding
A functional polymorphism in lnc-LAMC2-1:1 confers risk of colorectal cancer by affecting miRNA binding
复制标题
lnc-LAMC2-1:1 的功能多态性通过影响 miRNA 结合而增加结直肠癌的风险
DOI：
10.1093/carcin/bgw024
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发表时间：
2016-05-01
期刊：
影响因子：
4.7
通讯作者：
Miao, Xiaoping
中科院分区：
文献类型：
--
作者：
Gong, Jing;Tian, Jianbo;Miao, Xiaoping
LncRNAs在肿瘤的发生发展中起着重要作用。在此，我们发现rs2147578与中国人结直肠癌的发病风险显著相关，并且可能通过影响lnc-LAMC2-1：1/miR-128-3的结合而发挥作用。全基因组关联研究(GWASs)已经发现了结直肠癌的多个易感基因，然而，致病基因的多态还没有完全阐明。长非编码RNA(Long Non-Coding RNAs，LncRNAs)是新近发现的一类参与多种生物过程的非蛋白质编码RNAs。我们假设，lncRNA中的单核苷酸多态(SNPs)可能通过影响lncRNA的功能与结直肠癌风险相关。为了评价SNPs在中国人群中对结直肠癌易感性的影响，我们首先筛选了位于结直肠癌易感基因座的LncRNAs外显子上所有潜在功能的SNPs。在875例结直肠癌病例和855例对照中选择8个SNPs进行基因分型，并在由768例结直肠癌病例和768例对照组成的独立病例对照研究中重复。病例对照研究显示，与rs2147578 CC基因型相比，rs2147578的CG和GG基因型与结直肠癌发生的风险显著相关[联合分析OR=1.29；95%可信区间=1.11~1.51，P=0.001]。生物信息学分析表明，rs2147578位于lnc-LAMC2-1：1转录本上，可影响lnc-LAMC2-1：1/miR-128-3p的结合。进一步的荧光素酶报告分析表明，与rs2147578C等位基因相比，含有风险等位基因rs2147578G的构建体具有相对较高的表达活性。表达数量性状基因座分析还表明，rs2147578与已建立的癌基因LAMC2(层粘连蛋白亚基伽马2)的表达相关。提示LNC-LAMC2-1：1的rs2147578可能是结直肠癌发生的遗传修饰基因。
The lncRNAs play an important role in the occurrence and development of cancers. Here, we show that rs2147578 was significantly associated with increased risk for colorectal cancer in Chinese population and may exert its role by influencing the binding of lnc-LAMC2-1:1/miR-128-3p.Genome-wide association studies (GWASs) have identified multiple susceptibility loci of colorectal cancer (CRC), however, causative polymorphisms have not been fully elucidated. Long non-coding RNAs (lncRNAs) are a recently discovered class of non-protein coding RNAs that involved in a wide variety of biological processes. We hypothesized that single nucleotide polymorphisms (SNPs) in lncRNA may associate with the CRC risk by influencing lncRNA functions. To evaluate the effects of SNPs on CRC susceptibility in Chinese populations, we first screened out all potentially functional SNPs in exons of lncRNAs located in CRC susceptibility loci identified by GWAS. Eight SNPs were selected and genotyped in 875 CRC cases and 855 controls and replicated in an independent case-control study consisting of 768 CRC cases and 768 controls. Analyses showed that CG and GG genotypes of the rs2147578 were significantly associated with increased risk for CRC occurrence in both case-control studies [combined analysis OR = 1.29; 95% confidence interval (CI) = 1.11-1.51, P = 0.001] compared to the rs2147578 CC genotype. Bioinformatics analyses showed that rs2147578 is located in the transcript of lnc-LAMC2-1:1 and could influence the binding of lnc-LAMC2-1:1/miR-128-3p. Further luciferase reporter assays demonstrated that the construct with the risk rs2147578G allele had relatively high expression activity compared with that of the rs2147578C allele. Expression quantitative trait loci analyses also showed that rs2147578 is correlated with the expression of a well established oncogene LAMC2 (laminin subunit gamma 2). These findings indicated that rs2147578 in lnc-LAMC2-1:1 might be a genetic modifier for the development of CRC.