Identification of a functional SNP in the 3'UTR of CXCR2 that is associated with reduced risk of lung cancer.

Global changes in gene expression accompany the development of cancer. Thus, inherited variants in microRNA binding sites are likely candidates for conferring inherited susceptibility. Using an in-silico approach, we compiled a comprehensive list of SNPs predicted to modulate microRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in microRNA binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American (ORTT vs. CC 0.56 [0.37 – 0.88]; P=0.008) and Japanese (ORTT vs. CC 0.62 [0.38 – 1.00]; P=0.049) populations. Further, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL-8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL-8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3′UTR SNP in modulating CXCR2 expression, signaling and susceptibility to lung cancer.

基因表达的全球性变化伴随癌症的发展。因此，微小RNA（miRNA）结合位点的遗传变异很可能是导致遗传易感性的候选因素。我们采用计算机模拟方法，编制了一份全面的单核苷酸多态性（SNP）清单，这些SNP被预测可调节来自几个关键肺癌通路基因中的微小RNA结合。然后我们研究了这些SNP在两个独立人群中是否与肺癌风险相关。一般来说，微小RNA结合位点的SNP很罕见。然而，我们观察到了一些等位基因变异。我们发现CXCR2中的rs1126579在欧美人群（TT与CC相比，比值比为0.56[0.37 - 0.88]；P = 0.008）和日本人群（TT与CC相比，比值比为0.62[0.38 - 1.00]；P = 0.049）中都与肺癌风险降低相关。此外，我们发现该SNP破坏了miR - 516a - 3p的一个新结合位点，导致CXCR2的信使核糖核酸（mRNA）和蛋白质表达适度增加，并增强了丝裂原活化蛋白激酶（MAPK）信号传导。而且，对rs1126579与血清白细胞介素 - 8（IL - 8，其为内源性配体）水平的分析支持一种相互作用，即rs1126579 - T和高血清IL - 8赋予了对肺癌的协同保护作用。我们的研究结果证明了3′非翻译区（3′UTR）的一个SNP在调节CXCR2表达、信号传导以及对肺癌的易感性方面的作用。