A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer
A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer
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DOI：
10.1038/sj.onc.1209355
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发表时间：
2006-06-15
期刊：
影响因子：
8
通讯作者：
He, F.
中科院分区：
文献类型：
--
作者：
Hao, B.;Miao, X.;He, F.
X 射线修复交叉互补 1 (XRCC1) 在 DNA 碱基切除修复中发挥关键作用，缺乏其活性的细胞对 DNA 损伤高度敏感。最近，我们报道了 XRCC1 基因 5' 非翻译区 (UTR) 中的一个 SNP (rs3213245，-77T > C) 与发生食管鳞状细胞癌的风险显着相关。计算机分析预测该 SNP 位于 Sp1 结合基序的核心，这表明了其功能意义。凝胶位移和超位移测定证实 XRCC1 启动子中的 -77T > C 多态性位点位于 Sp1 结合基序内，并且 T > C 取代大大增强了 Sp1 与该区域的结合亲和力。荧光素酶测定表明 Sp1 高亲和力 C 等位基因 XRCC1 启动子与转录活性降低相关。在 1024 名患者和 1118 名对照者中检查了 -77T > C 和 XRCC1 中其他三种氨基酸取代引起的多态性与肺癌风险之间的关联，结果表明，只有 -77T > C 多态性与患肺癌风险增加显着相关。多变量 Logistic 回归分析发现，与 TT 基因型相比，XRCC1 -77 基因型（TC 和 CC）变异导致肺癌风险增加（OR 1.46，95% CI 1.18-1.82；P = 0.001），且吸烟者的风险增加更为明显（OR 1.63，95% CI 1.20-2.21）。非吸烟者（OR 1.28，95% CI 0.94-1.76）。总而言之，这些结果表明，XRCC1 5'UTR 中的功能性 SNP -77T > C 与癌症发展相关，因为含有 C 等位基因的启动子的转录活性降低，对 Sp1 结合具有更高的亲和力。
X-ray repair cross-complementing 1 (XRCC1) plays a key role in DNA base excision repair and cells lacking its activity are hypersensitive to DNA damage. Recently, we reported a SNP (rs3213245, -77T > C) in the XRCC1 gene 5' untranslated region (UTR) was significantly associated with the risk of developing esophageal squamous-cell carcinoma. Computer analysis predicted that this SNP was in the core of Sp1-binding motif, which suggested its functional significance. Gel shift and super shift assays confirmed that -77T > C polymorphic site in the XRCC1 promoter was within the Sp1-binding motif and the T > C substitution greatly enhanced the binding affinity of Sp1 to this region. Luciferase assays indicated that the Sp1-high-affinity C-allelic XRCC1 promoter was associated with a reduced transcriptional activity. The association between -77T > C and three other amino-acid substitution-causing polymorphisms in XRCC1 and risk of lung cancer was examined in 1024 patients and 1118 controls and the results showed that only the -77T > C polymorphism was significantly associated with an increased risk of developing lung cancer. Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR 1.46, 95% CI 1.18-1.82; P = 0.001) and the increased risk was more pronounced in smokers (OR 1.63, 95% CI 1.20-2.21) than in non-smokers (OR 1.28, 95% CI 0.94-1.76). Taken together, these results showed that the functional SNP -77T > C in XRCC1 5'UTR was associated with cancer development owing to the decreased transcriptional activity of C-allele-containing promoter with higher affinity to Sp1 binding.