环氧化酶-2功能性遗传变异与食管癌及胃癌易感性相关
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摘要
背景和目的：环氧化酶-2(COX-2)过表达与人类肿瘤发生发展密切相关。COX-2基因变异可能改变其表达水平和蛋白活性，从而影响宿主的肿瘤易感性。本研究筛查汉族人群COX-2基因功能性遗传变异并探讨其与食管癌和胃癌发病风险的关系。
方法：随机选择30个人外周血淋巴细胞DNA标本，分析COX-2基因的序列变异。以电泳迁移率变动实验(EMSA)、染色质免疫共沉淀(ChIP)实验、双荧光素酶报告基因实验和实时定量PCR、酶学实验等方法研究遗传变异的生物学功能。以多变量logistic回归计算基因型和单体型的病例-对照比值比(OR)及其95％可信区限(CI)。
结果：DNA测序发现5个单核苷酸多态，其中3个位于启动子区(-1290A→G、-1195G→A和-765G→C)，2个分别位于编码区(1759G→A或587Gly→Arg)和3′非翻译区(8473T→C)；变异等位基因频率均＞5％。EMSA、ChIP和报告基因实验结果显示，-1195G→A变异形成一转录因子c-MYB结合位点，A等位基因启动子驱动的报告基因表达水平显著高于G等位基因启动子驱动的报告基因表达水平。实时定量PCR分析显示，含-1195A等位基因单体型的食管组织中COX-2 mRNA含量显著高于含-1195G等位基因单体型的食管组织。587Gly→Arg氨基酸改变显著影响COX-2活性，COX-2-Arg~(587)催化花生四烯酸生成前列腺素的活性比COX-2-Gly~(587)高约1.5倍(P＜0.001)。8473T→C变异增加报告基因在食管癌细胞但不是胃癌细胞中的表达。病例-对照(食管癌1026例，胃癌680例，对照1270例)分析显示，-1195A、-765C和587Arg等位基因与食管癌和胃癌发病风险增高相关。8473C等位基因显著增加食管癌风险，但不增加胃癌风险。-1195A和-765C等位基因在单体型范畴内存在相乘交互作用。此外，启动子区3个单核苷酸多态与幽门螺杆菌感染有相乘的基因-环境交互作用共同增加胃癌发病风险。
结论：汉族人群COX-2基因存在功能性单核苷酸多态，显著影响COX-2的表达及其活性；这些功能性单核苷酸多态可能是食管癌和胃癌的遗传易感因素。
Background & Aims: Overexpression of cyclooxygenase-2 (COX-2) has been implicated in the development of many types of human cancer. Single nucleotide polymorphisms (SNPs) in the COX-2 gene might contribute to differential COX-2 expression and enzymatic activity. This study sought to identify SNPs located in the promoter region, coding region, and 3' untranslational region (3'UTR) of COX-2 and evaluated their effects on the biological functions of COX-2 and the risk of developing gastroesophageal cancer.
Methods: Thirty individual DNA samples isolated from peripheral blood lymphocytes were sequenced to search for SNPs of the COX-2 gene and the function of the SNPs in vitro were examined by electrophoretic mobility shift assays, luciferase reporter gene assays, chromatin immunoprecipitation assays, and enzymatic assays. The effects of the SNPs on the COX-2 mRNA expression in vivo in esophageal tissues were determined by real-time quantitative PCR. Genotypes and haplotypes were analyzed in 1026 patients with esophageal cancer, 680 patients with gastric cancer, and 1270 controls, and odds ratios and 95% confidence intervals were estimated by logistic regression.
Results: Five SNPs were identified in the COX-2 gene, with the minor allelic frequencies being >5%. Among these SNPs, three (-1290A→G, -1195G→A and -765G→C) are located in the promoter region and two are respectively located in the coding region (587Gly→Arg) and 3'UTR (8473T→C). The -1195G→A change creates a c-MYB binding site and displays a higher promoter activity. The -1195A-containing haplotypes had significantly increased luciferase expression and COX-2 mRNA levels in esophageal tissues compared with the -1195G-containing counterparts. The 587Gly→Arg change had significant impact on COX-2 activity; the COX-2-Arg~(587) isoform showed 1.5-fold elevated enzymatic activity than the COX-2-Gly~(587) isoform in converting arachidonic acid into prostaglandins. The 8473C variant also had significant effect on luciferase gene expression in esophageal cancer cell KYSE150 but not gastric cancer cell MGC803. A case-control analysis showed an excess risk of developing esophageal cancer and gastric cancer for the
方法：随机选择30个人外周血淋巴细胞DNA标本，分析COX-2基因的序列变异。以电泳迁移率变动实验(EMSA)、染色质免疫共沉淀(ChIP)实验、双荧光素酶报告基因实验和实时定量PCR、酶学实验等方法研究遗传变异的生物学功能。以多变量logistic回归计算基因型和单体型的病例-对照比值比(OR)及其95％可信区限(CI)。
结果：DNA测序发现5个单核苷酸多态，其中3个位于启动子区(-1290A→G、-1195G→A和-765G→C)，2个分别位于编码区(1759G→A或587Gly→Arg)和3′非翻译区(8473T→C)；变异等位基因频率均＞5％。EMSA、ChIP和报告基因实验结果显示，-1195G→A变异形成一转录因子c-MYB结合位点，A等位基因启动子驱动的报告基因表达水平显著高于G等位基因启动子驱动的报告基因表达水平。实时定量PCR分析显示，含-1195A等位基因单体型的食管组织中COX-2 mRNA含量显著高于含-1195G等位基因单体型的食管组织。587Gly→Arg氨基酸改变显著影响COX-2活性，COX-2-Arg~(587)催化花生四烯酸生成前列腺素的活性比COX-2-Gly~(587)高约1.5倍(P＜0.001)。8473T→C变异增加报告基因在食管癌细胞但不是胃癌细胞中的表达。病例-对照(食管癌1026例，胃癌680例，对照1270例)分析显示，-1195A、-765C和587Arg等位基因与食管癌和胃癌发病风险增高相关。8473C等位基因显著增加食管癌风险，但不增加胃癌风险。-1195A和-765C等位基因在单体型范畴内存在相乘交互作用。此外，启动子区3个单核苷酸多态与幽门螺杆菌感染有相乘的基因-环境交互作用共同增加胃癌发病风险。
结论：汉族人群COX-2基因存在功能性单核苷酸多态，显著影响COX-2的表达及其活性；这些功能性单核苷酸多态可能是食管癌和胃癌的遗传易感因素。
Background & Aims: Overexpression of cyclooxygenase-2 (COX-2) has been implicated in the development of many types of human cancer. Single nucleotide polymorphisms (SNPs) in the COX-2 gene might contribute to differential COX-2 expression and enzymatic activity. This study sought to identify SNPs located in the promoter region, coding region, and 3' untranslational region (3'UTR) of COX-2 and evaluated their effects on the biological functions of COX-2 and the risk of developing gastroesophageal cancer.
Methods: Thirty individual DNA samples isolated from peripheral blood lymphocytes were sequenced to search for SNPs of the COX-2 gene and the function of the SNPs in vitro were examined by electrophoretic mobility shift assays, luciferase reporter gene assays, chromatin immunoprecipitation assays, and enzymatic assays. The effects of the SNPs on the COX-2 mRNA expression in vivo in esophageal tissues were determined by real-time quantitative PCR. Genotypes and haplotypes were analyzed in 1026 patients with esophageal cancer, 680 patients with gastric cancer, and 1270 controls, and odds ratios and 95% confidence intervals were estimated by logistic regression.
Results: Five SNPs were identified in the COX-2 gene, with the minor allelic frequencies being >5%. Among these SNPs, three (-1290A→G, -1195G→A and -765G→C) are located in the promoter region and two are respectively located in the coding region (587Gly→Arg) and 3'UTR (8473T→C). The -1195G→A change creates a c-MYB binding site and displays a higher promoter activity. The -1195A-containing haplotypes had significantly increased luciferase expression and COX-2 mRNA levels in esophageal tissues compared with the -1195G-containing counterparts. The 587Gly→Arg change had significant impact on COX-2 activity; the COX-2-Arg~(587) isoform showed 1.5-fold elevated enzymatic activity than the COX-2-Gly~(587) isoform in converting arachidonic acid into prostaglandins. The 8473C variant also had significant effect on luciferase gene expression in esophageal cancer cell KYSE150 but not gastric cancer cell MGC803. A case-control analysis showed an excess risk of developing esophageal cancer and gastric cancer for the
引文
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