Genetic variants at the miR-124 binding site on the cytoskeleton-organizing IQGAP1 gene confer differential predisposition to breast cancer
Genetic variants at the miR-124 binding site on the cytoskeleton-organizing IQGAP1 gene confer differential predisposition to breast cancer
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细胞骨架组织 IQGAP1 基因上 miR-124 结合位点的遗传变异赋予乳腺癌不同的易感性
DOI：
10.3892/ijo.2011.940
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发表时间：
2011-04-01
影响因子：
5.2
通讯作者：
Chen, Kexin
中科院分区：
文献类型：
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作者：
Zheng, Hong;Song, Fengju;Chen, Kexin
IQGAP1基因敲除的小鼠会患上胃癌，但IQGAP1蛋白与一些晚期人类癌症有关。IQGAP1的表达受微小RNA miR-124的调控，通过3‘-非翻译区的结合位点，在核心结合区存在单核苷酸多态(SNP)。我们询问IQGAP1的表达是否与乳腺癌的发生有关，以及miR-124结合位点的遗传变异是否重要。我们在1,541例乳腺癌患者和1,598名对照中对IQGAP1 SNP rs1042538A/T进行了基因分型，并分析了该变异的频率及其与主要危险因素的交互作用。我们还检测了不同IQGAP1基因在mRNA和蛋白水平上的表达。IQGAP1TT型与AA型相比，患乳腺癌的风险显著降低[P=0.049，优势比(OR)0.78；95%可信区间(CI)0.61~0.99]在单纯病例分析中，TT型与AA型相比与孕激素受体阳性者有关联(OR=1.35；95%CI，1.00~1.83)。TT型IQGAP I蛋白表达水平显著高于AA型。MiR-124结合位点上SNPs的存在可能是预测乳腺癌风险和预后的一个标志。
IQGAP1 knockout mice develop gastric cancer, but the IQGAP1 protein is associated with some advanced-stage human cancers. IQGAP1 expression is regulated by a microRNA, miR-124, through a binding site at the 3'-untranslated region, where a single nucleotide polymorphism (SNP) exists in the core binding region. We asked whether IQGAP1 expression is associated with breast cancer development and whether genetic variants at the miR-124 binding site are important. We genotyped the IQGAP1 SNP rs1042538 A/T in 1,541 breast cancer cases and 1,598 controls and analyzed the frequency of the variant and interactions with major risk factors in these populations. We also measured the expression of IQGAP1 at both mRNA and protein levels in different IQGAP1 genotypes. The IQGAP1 TT genotype, compared with the AA genotype, was associated with a significantly lower risk of developing breast cancer [P=0.049, odds ratio (OR), 0.78; 95% confidence interval (CI), 0.61-0.99] In case-only analyses, the TT, compared with the AA, genotype was associated with progesterone receptor-positive subjects (OR, 1.35; 95% CI, 1.00-1.83). The expression levels of IQGAP I protein were significantly higher in the TT genotype compated to the AA genotype. The presence of SNPs at the miR-124 binding site may be a marker for predicting breast cancer risk and prognosis.