A novel functional variant (-842G>C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity
A novel functional variant (-842G>C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity
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DOI：
10.1093/carcin/bgp171
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发表时间：
2009-10-01
期刊：
影响因子：
4.7
通讯作者：
Wei, Qingyi
中科院分区：
文献类型：
--
作者：
Lu, Jiachun;Hu, Zhibin;Wei, Qingyi
Pin1是一种新的肽基-脯氨酰顺/反式异构酶，它调节Pro导向的磷酸化位点的构象，揭示了一种新的磷酸化后调控机制。Pin1诱导的构象变化增强了多种致癌信号通路，Pin1的过度表达被认为是人类癌症中普遍存在的一种特异事件。在这项研究中，我们验证了Pin1编码区和启动子区域常见的多态性与头颈部鳞状细胞癌(SCCHN)风险相关的假设。在一项基于医院的病例对照研究中，我们对1006例SCCHN患者和1007例非肿瘤对照受试者进行了PIN1基因-842G>；C、-667T>；C和Gln33Gln基因分型。我们发现-842C变异基因与SCCHN的风险降低相关[与GG基因相比，CC型的优势比(OR)=0.74，95%可信区间(CI)=0.59~0.93，OR=0.82；CC型的95%CI=0.34~2.01；CG+CC型的OR=0.74；95%CI=0.59~0.93]。然而，没有观察到-667T>；C和Gln33Gln多态的风险改变。进一步的由等位基因Pin1启动子驱动的报告基因表达实验表明，-842G等位基因比-842C等位基因具有更高的活性，这表明-842C等位基因与转录活性降低有关，这一发现与病例对照分析中观察到的降低风险一致。对不同种族和不同癌症部位进行的大型前瞻性研究是有根据的，以验证我们的发现。
PIN1, a new peptidyl-prolyl cis/trans isomerase, regulates the conformation of Pro-directed phosphorylation sites, revealing a new postphosphorylation regulatory mechanism. PIN1-induced conformational changes potentiate multiple oncogenic signaling pathways, and PIN1 overexpression is reported as a prevalent and specific event in human cancers. In this study, we tested the hypothesis that common polymorphisms in the coding and promoter regions of PIN1 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We genotyped three selected PIN1 polymorphisms (-842G > C, -667T > C and Gln33Gln) in a hospital-based case-control study of 1006 patients with SCCHN and 1007 cancer-free control subjects. We found that the -842C variant genotypes were associated with decreased risk for SCCHN [Odds Ratio (OR) = 0.74; 95% confidence interval (CI) = 0.59-0.93 for the CG genotype, OR = 0.82; 95% CI = 0.34-2.01 for the CC genotype and OR = 0.74; 95% CI = 0.59-0.93 for CG+CC genotypes, compared with the GG genotype]. However, no altered risks were observed for -667T > C and Gln33Gln polymorphisms. Further experiments of the reporter gene expression driven by the allelic PIN1 promoter showed that the -842G allele had a higher activity than that driven by the -842C allele, suggesting that the -842C allele was associated with a reduced transcriptional activity, a finding consistent with a reduced risk observed in the case-control analysis. Large prospective studies of diverse ethnic groups and diverse cancer sites are warranted to validate our findings.