A functional polymorphism in the 3'-UTR of PXR interacts with smoking to increase lung cancer risk in southern and eastern Chinese smoker.
A functional polymorphism in the 3'-UTR of PXR interacts with smoking to increase lung cancer risk in southern and eastern Chinese smoker.
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DOI：
10.3390/ijms151017457
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发表时间：
2014-09-29
影响因子：
5.6
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Zhang L;Qiu F;Lu X;Li Y;Fang W;Zhang L;Zhou Y;Yang L;Lu J
孕烷X受体（PXR）是核受体超家族的重要成员，它通过调控一系列环境应答基因，应对各种内源性和外源性刺激，如致癌物。已有研究表明，PXR表达水平低会促进肿瘤的起始和转移。本研究旨在探究PXR的单核苷酸多态性（SNP）是否会通过影响PXR的功能或表达，改变中国人群患肺癌的易感性。我们对PXR的三个假定具有功能的SNP（即rs3814055C>T、rs3732360C>T和rs3814058C>T）进行基因分型，并在一项两阶段病例对照研究中分析它们与肺癌风险的关联，该研究纳入了中国南方和东部地区共1559例肺癌患者和1679例对照。我们发现，与常见基因型rs3814058CC相比，位于PXR 3'-非翻译区（3'-UTR）的rs3814058T变异型（TC/TT）在中国南方人群（比值比（OR） = 1.24，95%置信区间（CI） = 1.03 - 1.49）和中国东部人群（OR = 1.33，95%CI = 1.02 - 1.75）中均一致增加了患肺癌的风险。该变异型与吸烟在增加癌症风险方面也存在显著交互作用（p = 0.023）。此外，在吸烟者中，携带rs3814058T变异型的肺癌组织，其PXR表达水平显著低于携带rs3814058CC基因型的肺癌组织（p = 0.041）。这些结果表明，PXR的rs3814058C>T多态性与吸烟相互作用，增加了中国吸烟者患肺癌的风险，这可能是肺癌的一个功能性遗传生物标志物。
Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and metastasis. The aim of the current study was to investigate whether the single nucleotide polymorphisms (SNPs) of PXR could alter lung cancer susceptibility in Chinese by affecting the function or expression of PXR. We genotyped three putatively functional SNPs of PXR (i.e., rs3814055C>T, rs3732360C>T, and rs3814058C>T) and analyzed their associations with lung cancer risk in a two-stage case-control study with a total of 1559 lung cancer cases and 1679 controls in the southern and eastern Chinese population. We found that in comparison to the rs3814058CC common genotype, the rs3814058T variants (TC/TT) which is located in the 3'-untranslated region (3'-UTR) of PXR conferred a consistently increased risk of lung cancer in both the southern Chinese (odd ratios (OR) = 1.24, 95% confidence interval (CI) = 1.03−1.49) and the eastern Chinese (OR = 1.33, 95% CI = 1.02−1.75). The variants also significantly interacted with smoking on increasing cancer risk (p = 0.023). Moreover, lung cancer tissues with the rs3814058T variants showed significantly lower PXR expression than those with rs3814058CC genotype in the smokers (p = 0.041). These results suggested that the rs3814058C>T polymorphism of PXR interacts with smoking on increasing lung cancer risk in Chinese smokers, which might be a functional genetic biomarker for lung cancer.
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