环氧化酶-2遗传变异和吸烟交互作用与胰腺癌—核仁磷酸蛋白的作用
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摘要
目的:COX-2与胰腺癌发生发展密切相关,本研究探讨COX-2基因启动子区遗传变异与胰腺癌遗传易感性的关系及其在吸烟与胰腺癌发病中的作用。
方法:研究对象为393例胰腺癌患者和786例健康对照。COX-2启动子区-765G/C、-1195G/A和-1290A/G基因型用PCR-限制性片段长度多态方法测定,以多因素logistic回归分析基因型及吸烟等危险因素与胰腺癌发生风险的关系;用双荧光素酶报告基因实验研究不同基因型COX-2启动子在香烟浓缩物刺激时的表达活性;用凝胶电泳迁移率变动实验和染色质免疫共沉淀实验分析与不同等位基因结合的细胞核蛋白(转录因子),并用基质辅助激光解析电离飞行时间质谱鉴定其成分;用蛋白质免疫印迹实验、细胞免疫荧光和RNA干扰实验探讨香烟浓缩物刺激时核仁磷酸蛋白(nucleophosmin,NPM)与COX-2蛋白表达之间的关系。
结果:COX-2启动子区-1195G/A和-765G/C遗传变异与胰腺癌发病风险相关,-1195AA和-765CG基因型携带者发生胰腺癌风险显著高于-1195GG和-765GG基因型携带者(OR=1.34;95%CI=1.12-1.60和OR=1.63;95%CI=1.25-2.10)。单体型分析结果显示这两个遗传变异之间有协同作用,A_(-1195)-C_(-765)单体型携带者发生胰腺癌风险显著高于G_(-1195)-G_(-765)单体型携带者。吸烟也是胰腺癌的危险因素(OR=1.48;95%CI=1.26-1.74),而且与-765G/C变异存在高于相乘的交互作用。-765CG基因型的重度吸烟者患胰腺癌的OR为3.72(95%CI=1.70-8.14),高于-765GG基因型吸烟者(OR=1.43;95%CI=1.21-1.69)和-765GC基因型不吸烟者(OR=1.44;95%CI=1.04-1.99)OR值的乘积(3.72＞1.43×1.44)。报告基因实验结果表明不同-765等位基因的基础表达水平无统计学显著差异,但在香烟浓缩物刺激后,-765C等位基因的表达高于-765G等位基因。凝胶电泳迁移率变动实验结果显示,不同的-765等位基因结合的核蛋白不同,质谱鉴定及超迁移实验证明与-765C等位基因结合的核蛋白为磷酸化的NPM。经香烟浓缩物刺激后,细胞核内磷酸化NPM水平降低,结合于COX-2启动子区的磷酸化NPM也下降,但敲降NPM表达后COX-2蛋白表达水平降低。这些结果提示,磷酸化NPM特异性结合于-765C等位基因对COX-2的表达起抑制作用,香烟浓缩物刺激后磷酸化NPM减少,从而使-765C等位基因表达高于-765G等位基因。
结论:COX-2启动子区遗传变异与胰腺癌遗传易感性相关,-765G/C变异与吸烟有显著的交互作用,共同增加胰腺癌发病风险,其作用机制可能是由磷酸化NPM介导。
Background & Aim:Pancreatic cancer is a big health problem and challenge for cancer research due to the increasing incidence and extremely poor prognosis of this lethality disease.The mechanism of pancreatic cancer is largely unknown and the only established etiology is tobacco smoking.Over expression of cyclooxygenase-2(COX-2) is implicated in pancreatic cancer development and cigarette smoking can induce the expression of this enzyme.This study examined the interaction of genetic polymorphisms of the COX-2 promoter and smoking in susceptibility to pancreatic cancer and the functional relevance.
Methods:Genotypes and haplotypes of COX-2-765G/C,-1195G/A and-1290A/G were analyzed in 393 pancreatic cancer patients and 786 controls.Odds ratio(OR) and 95%confidence interval(CI) were computed by logistic regression.The function of the -765G/C polymorphism was examined by a set of biochemical assays.Dual luciferase reporter assays were performed to compare the COX-2 promoter activity of different alleles by transient transfection of reporter vectors into human pancreatic cancer cell lines PANC-1,AsPC-1 and human colon cancer cell line HCT-116 with or without the stimulation of cigarette smoke condenses.Electrophoretic mobility shift assay(EMSA) was carried out to examine the differential nuclear proteins binding to the-765G/C site and the proteins were purified and identified by a matrix assisted laser desorption ionisation time-of-flight mass spectrometry(MALDI-TOF-MS) and verified by supershift assay.Chromatin immunoprecipitation assay(CHIP),immunofluorescent staining and confocal imaging,western blot and RNA interference were employed to investigate the regulation of COX-2 expression by the verified nuclear protein.
Results:The-1195AA or-765GC genotype carriers had a 1.34-fold(95%CI= 1.12-1.60) or 1.63-fold(95%CI=1.25-2.10) excess risk for developing pancreatic cancer.These two variants showed a cooperative effect in context of haplotype,with the ORs for the A_(-1195)-C_(-765)-containing haplotypes being significantly greater than those for the G_(-1195)-G_(-765)-containing haplotypes.Smoking also increased pancreatic cancer risk, with the OR being 1.48(95%CI=1.26-1.74).The-765C allele and smoking displayed a multiplicative joint effect,with the OR being 3.72(95%CI=1.70-8.14) for heavy smokers carrying the -765GC genotype.Dual luciferase reporter assays showed that cigarette smoke remarkably increased COX-2 promoter activity and this effect was more pronounced for the -765C allele-containing reporter plasmid compared with the -765G allele-containing counterpart.The differential nuclear protein binding to the -765C allele found in EMSA was identified as nucleophosmin(NPM) by MALDI-TOF-MS and verified by antibody against phosphorylated NPM(p-NPM) in supershift assay.Western blot and immunofluorescence staining analysis revealed that cigarette smoke reduced nuclear NPM levels,especially p-NPM levels,which was reversely associated with COX-2 expression.Knock-down of NPM by RNAi leads to decrease in COX-2 protein expression.ChIP assay with antibody against NPM or p-NPM indicated that cigarette smoke reduced nuclear p-NPM levels,which was reversely associated with COX-2 expression by reducing the p-NPM binding to the -765 site of COX-2 promoter, suggesting that the -765G to C change creates a binding site for p-NPM,which acts as a transcriptional inhibitor.
Conclusion:Functional COX-2 polymorphisms are associated with susceptibility to pancreatic cancer and tobacco smoke specifically increases -765C promoter activity, which might be mediated by p-NPM.
方法:研究对象为393例胰腺癌患者和786例健康对照。COX-2启动子区-765G/C、-1195G/A和-1290A/G基因型用PCR-限制性片段长度多态方法测定,以多因素logistic回归分析基因型及吸烟等危险因素与胰腺癌发生风险的关系;用双荧光素酶报告基因实验研究不同基因型COX-2启动子在香烟浓缩物刺激时的表达活性;用凝胶电泳迁移率变动实验和染色质免疫共沉淀实验分析与不同等位基因结合的细胞核蛋白(转录因子),并用基质辅助激光解析电离飞行时间质谱鉴定其成分;用蛋白质免疫印迹实验、细胞免疫荧光和RNA干扰实验探讨香烟浓缩物刺激时核仁磷酸蛋白(nucleophosmin,NPM)与COX-2蛋白表达之间的关系。
结果:COX-2启动子区-1195G/A和-765G/C遗传变异与胰腺癌发病风险相关,-1195AA和-765CG基因型携带者发生胰腺癌风险显著高于-1195GG和-765GG基因型携带者(OR=1.34;95%CI=1.12-1.60和OR=1.63;95%CI=1.25-2.10)。单体型分析结果显示这两个遗传变异之间有协同作用,A_(-1195)-C_(-765)单体型携带者发生胰腺癌风险显著高于G_(-1195)-G_(-765)单体型携带者。吸烟也是胰腺癌的危险因素(OR=1.48;95%CI=1.26-1.74),而且与-765G/C变异存在高于相乘的交互作用。-765CG基因型的重度吸烟者患胰腺癌的OR为3.72(95%CI=1.70-8.14),高于-765GG基因型吸烟者(OR=1.43;95%CI=1.21-1.69)和-765GC基因型不吸烟者(OR=1.44;95%CI=1.04-1.99)OR值的乘积(3.72＞1.43×1.44)。报告基因实验结果表明不同-765等位基因的基础表达水平无统计学显著差异,但在香烟浓缩物刺激后,-765C等位基因的表达高于-765G等位基因。凝胶电泳迁移率变动实验结果显示,不同的-765等位基因结合的核蛋白不同,质谱鉴定及超迁移实验证明与-765C等位基因结合的核蛋白为磷酸化的NPM。经香烟浓缩物刺激后,细胞核内磷酸化NPM水平降低,结合于COX-2启动子区的磷酸化NPM也下降,但敲降NPM表达后COX-2蛋白表达水平降低。这些结果提示,磷酸化NPM特异性结合于-765C等位基因对COX-2的表达起抑制作用,香烟浓缩物刺激后磷酸化NPM减少,从而使-765C等位基因表达高于-765G等位基因。
结论:COX-2启动子区遗传变异与胰腺癌遗传易感性相关,-765G/C变异与吸烟有显著的交互作用,共同增加胰腺癌发病风险,其作用机制可能是由磷酸化NPM介导。
Background & Aim:Pancreatic cancer is a big health problem and challenge for cancer research due to the increasing incidence and extremely poor prognosis of this lethality disease.The mechanism of pancreatic cancer is largely unknown and the only established etiology is tobacco smoking.Over expression of cyclooxygenase-2(COX-2) is implicated in pancreatic cancer development and cigarette smoking can induce the expression of this enzyme.This study examined the interaction of genetic polymorphisms of the COX-2 promoter and smoking in susceptibility to pancreatic cancer and the functional relevance.
Methods:Genotypes and haplotypes of COX-2-765G/C,-1195G/A and-1290A/G were analyzed in 393 pancreatic cancer patients and 786 controls.Odds ratio(OR) and 95%confidence interval(CI) were computed by logistic regression.The function of the -765G/C polymorphism was examined by a set of biochemical assays.Dual luciferase reporter assays were performed to compare the COX-2 promoter activity of different alleles by transient transfection of reporter vectors into human pancreatic cancer cell lines PANC-1,AsPC-1 and human colon cancer cell line HCT-116 with or without the stimulation of cigarette smoke condenses.Electrophoretic mobility shift assay(EMSA) was carried out to examine the differential nuclear proteins binding to the-765G/C site and the proteins were purified and identified by a matrix assisted laser desorption ionisation time-of-flight mass spectrometry(MALDI-TOF-MS) and verified by supershift assay.Chromatin immunoprecipitation assay(CHIP),immunofluorescent staining and confocal imaging,western blot and RNA interference were employed to investigate the regulation of COX-2 expression by the verified nuclear protein.
Results:The-1195AA or-765GC genotype carriers had a 1.34-fold(95%CI= 1.12-1.60) or 1.63-fold(95%CI=1.25-2.10) excess risk for developing pancreatic cancer.These two variants showed a cooperative effect in context of haplotype,with the ORs for the A_(-1195)-C_(-765)-containing haplotypes being significantly greater than those for the G_(-1195)-G_(-765)-containing haplotypes.Smoking also increased pancreatic cancer risk, with the OR being 1.48(95%CI=1.26-1.74).The-765C allele and smoking displayed a multiplicative joint effect,with the OR being 3.72(95%CI=1.70-8.14) for heavy smokers carrying the -765GC genotype.Dual luciferase reporter assays showed that cigarette smoke remarkably increased COX-2 promoter activity and this effect was more pronounced for the -765C allele-containing reporter plasmid compared with the -765G allele-containing counterpart.The differential nuclear protein binding to the -765C allele found in EMSA was identified as nucleophosmin(NPM) by MALDI-TOF-MS and verified by antibody against phosphorylated NPM(p-NPM) in supershift assay.Western blot and immunofluorescence staining analysis revealed that cigarette smoke reduced nuclear NPM levels,especially p-NPM levels,which was reversely associated with COX-2 expression.Knock-down of NPM by RNAi leads to decrease in COX-2 protein expression.ChIP assay with antibody against NPM or p-NPM indicated that cigarette smoke reduced nuclear p-NPM levels,which was reversely associated with COX-2 expression by reducing the p-NPM binding to the -765 site of COX-2 promoter, suggesting that the -765G to C change creates a binding site for p-NPM,which acts as a transcriptional inhibitor.
Conclusion:Functional COX-2 polymorphisms are associated with susceptibility to pancreatic cancer and tobacco smoke specifically increases -765C promoter activity, which might be mediated by p-NPM.
引文
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