Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility.
Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility.
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DOI：
10.1158/0008-5472.can-09-3541
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Calin GA
中科院分区：
文献类型：
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作者：
Nicoloso MS;Sun H;Spizzo R;Kim H;Wickramasinghe P;Shimizu M;Wojcik SE;Ferdin J;Kunej T;Xiao L;Manoukian S;Secreto G;Ravagnani F;Wang X;Radice P;Croce CM;Davuluri RV;Calin GA
与乳腺癌（BC）等多遗传疾病相关的单核苷酸多态性（snp）可以产生、破坏或修饰microRNA （miRNA）结合位点；然而，SNPs干扰miRNA基因调控并影响癌症易感性的程度在很大程度上仍然未知。我们假设SNPsis破坏miRNA靶标结合是与癌症易感性相关的广泛机制。为了验证这一点，我们分析了已知的与BC风险相关的SNPs，在硅和体外，因为它们能够修改miRNA结合位点和miRNA基因调控，并将这些称为靶SNPs。我们鉴定出rs1982073-TGFB1和rs1799782-XRCC1作为靶snp，其等位基因分别通过与miR-187和miR-138的差异相互作用来调节基因表达。全基因组生物信息学分析预测，大约64%的转录snp作为目标snp可以修饰（增加/减少）假定的miRNA::mRNA双链的结合能超过90%。为了评估目标snp是否与BC易感性有关，我们进行了一项病例对照人群研究，观察到rs799917-BRCA1和rs334348-TGFR1的种系发生率在发生BC的不同风险人群中存在显著差异。在不同基因型的癌细胞系中，靶snp等位基因变异的荧光素酶活性和蛋白水平显示，过表达两种相互作用的mirna （miR-638和miR-628-5p）后，靶基因的调控存在差异。因此，我们提出转录的目标snp通过微妙的基因调控新机制改变miRNA基因调控，从而改变蛋白质表达，从而增加癌症易感性的可能性。
Single nucleotide polymorphisms (SNPs) associated with polygenetic disorders, such as breast cancer (BC), can create, destroy or modify microRNA (miRNA) binding sites; however, the extent to which SNPs interfere with miRNA gene regulation and affect cancer susceptibility remains largely unknown. We hypothesize that disruption of miRNA target binding by SNPsis a widespread mechanism relevant to cancer susceptibility. In order to test this, we analyzed SNPs known to be associated with BC risk, in silico and in vitro, for their ability to modify miRNA binding sites and miRNA gene regulation and referred to these as target SNPs. We identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs, whose alleles could modulate gene expression by differential interaction with miR-187 and miR-138, respectively. Genome-wide bioinformatics analysis predicted approximately 64% of transcribed SNPs as target SNPs that can modify (increase/decrease) the binding energy of putative miRNA::mRNA duplexes by over 90%. To assess whether target SNPs are implicated in BC susceptibility, we conducted a case-control population study and observed that germline occurrence of rs799917-BRCA1 and rs334348-TGFR1, significantly varies among populations with different risks of developing BC. Luciferase activity of target SNPs allelic variants and protein levels in cancer cell lines with different genotypes showed differential regulation of target genes following over-expression of the two interacting miRNAs (miR-638 and miR-628-5p). Therefore, we propose that transcribed target SNPs alter miRNA gene regulation and consequently protein expression, contributing to the likelihood of cancer susceptibility, by a novel mechanism of subtle gene regulation.