Zhang Gui-Ming, Wang Meng-Yun, Liu Ya-Nan, Zhu Yao, Wan Fang-Ning, Wei Qing-Yi, Ye Ding-Wei
Department of Urology, The Affiliated Hospital of Qingdao University, China.
Department of Urology, Fudan University Shanghai Cancer Center, China.
Carcinogenesis. 2017 Dec 7;38(12):1241-1248. doi: 10.1093/carcin/bgx098.
Recent studies indicate that abnormal levels of low-density lipoprotein (LDL), which is an important component of dyslipidaemia, are associated with alterations to cancer risk, including that of renal cell carcinoma (RCC). Single nucleotide polymorphisms at microRNA-binding sites contribute to cancer susceptibility and progression by affecting the messenger RNA (mRNA) function of target genes. In this case-control study, we examined the frequency of six potentially functional single nucleotide polymorphisms in the LDL receptor gene (LDLR) in 1004 clear cell RCC (ccRCC) patients and 1065 cancer-free subjects. Logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs). The association between genetic variants and levels of LDLR mRNA and protein was also evaluated. Compared with the CC genotype, multivariate logistic regression analysis showed that the LDLR rs2738464 variant GG genotype was associated with a significantly decreased ccRCC risk (P = 0.002, OR: 0.605, 95% CI: 0.439-0.833). Further functional experiments showed that the rs2738464 variant G allele affected miR-330 regulation of the LDLR 3'-untranslated region (UTR), increasing LDLR mRNA levels in patient kidney tissues. These findings suggest that LDLR rs2738464 may affect the affinity of miR-330 binding to the LDLR 3'-UTR, thus regulating LDLR expression and contributing to ccRCC risk.
近期研究表明，低密度脂蛋白（LDL）水平异常是血脂异常的一个重要组成部分，与癌症风险的改变有关，包括肾细胞癌（RCC）。微小RNA结合位点的单核苷酸多态性通过影响靶基因的信使核糖核酸（mRNA）功能，对癌症易感性和进展产生影响。在这项病例对照研究中，我们检测了1004例透明细胞肾细胞癌（ccRCC）患者和1065例无癌受试者中低密度脂蛋白受体基因（LDLR）六个潜在功能性单核苷酸多态性的频率。逻辑回归分析估计了比值比（OR）和95%置信区间（CI）。还评估了基因变异与LDLR mRNA和蛋白质水平之间的关联。与CC基因型相比，多变量逻辑回归分析显示，LDLR rs2738464变异体GG基因型与ccRCC风险显著降低相关（P = 0.002，OR：0.605，95% CI：0.439 - 0.833）。进一步的功能实验表明，rs2738464变异体G等位基因影响miR - 330对LDLR 3'非翻译区（UTR）的调控，增加了患者肾组织中LDLR mRNA水平。这些发现表明，LDLR rs2738464可能影响miR - 330与LDLR 3' - UTR结合的亲和力，从而调节LDLR表达并影响ccRCC风险。
