Cao Qiang, Wang Jian, Zhang Mingcong, Li Pu, Qian Jian, Zhang Shaobo, Zhang Lei, Ju Xiaobing, Wang Meilin, Zhang Zhengdong, Li Jie, Gu Min, Zhang Wei, Qin Chao, Shao Pengfei, Yin Changjun
State Key Laboratory of Reproductive Medicine, Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
PLoS One. 2014 Oct 16;9(10):e109285. doi: 10.1371/journal.pone.0109285. eCollection 2014.
Raf-1 kinase inhibitor protein (RKIP) plays a critical role in tumor development by regulating cell functions such as invasion, apoptosis and differentiation. Down-regulation of RKIP expression has been implicated in the development and progression of renal cell carcinoma (RCC). Herein, we hypothesized that genetic polymorphisms in RKIP might be associated with susceptibility and progression of RCC.
A total of 5 tagging single-nucleotide polymorphisms (tSNPs) in RKIP were selected and genotyped by SNapShot method in a case-control study of 859 RCC patients and 1004 controls. The logistic regression was used to evaluate the genetic association with occurrence and progression of RCC. The functionality of the important SNP was preliminary examined by qRT-PCR.
We found that the rs17512051 in the promoter region of RKIP was significantly associated with decreased clear cell RCC (ccRCC) risk (TA/AA vs. TT: P = 0.039, OR = 0.78, 95%CI = 0.62-0.99). Another SNP (rs1051470) in the 3'UTR region of RKIP was marginally associated with increased ccRCC risk (TT vs. CC+CT: OR = 1.45, 95%CI = 1.01-2.09). In the stratified analysis, the protective effect of rs17512051 was more predominant in the subgroups of male, non-smokers, non-drinkers as well as subjects without history of diabetes. Furthermore, we observed higher RKIP mRNA levels in the presence of the rs17512051A allele in normal renal tissues.
Our results suggest that the potentially functional RKIP rs17512051 polymorphism may affect ccRCC susceptibility through altering the endogenous RKIP expression level. Risk effects and the functional impact of this polymorphism need further validation.
Raf-1激酶抑制蛋白（RKIP）通过调节细胞侵袭、凋亡和分化等功能，在肿瘤发展中发挥关键作用。RKIP表达下调与肾细胞癌（RCC）的发生和进展有关。在此，我们假设RKIP基因多态性可能与RCC的易感性和进展相关。
在一项包含859例RCC患者和1004例对照的病例对照研究中，通过SNapShot方法对RKIP中的5个标签单核苷酸多态性（tSNP）进行基因分型。采用逻辑回归评估与RCC发生和进展的遗传关联。通过qRT-PCR初步检测重要SNP的功能。
我们发现RKIP启动子区域的rs17512051与透明细胞RCC（ccRCC）风险降低显著相关（TA/AA与TT相比：P = 0.039，OR = 0.78，95%CI = 0.62 - 0.99）。RKIP 3'UTR区域的另一个SNP（rs1051470）与ccRCC风险增加存在边缘关联（TT与CC + CT相比：OR = 1.45，95%CI = 1.01 - 2.09）。在分层分析中，rs17512051的保护作用在男性、不吸烟者、不饮酒者以及无糖尿病史的亚组中更为显著。此外，我们观察到正常肾组织中存在rs17512051A等位基因时，RKIP mRNA水平较高。
我们的结果表明，潜在功能性的RKIP rs17512051多态性可能通过改变内源性RKIP表达水平影响ccRCC易感性。这种多态性的风险效应和功能影响需要进一步验证。
