醛固酮还原酶(Aldo-keto reductase family 1 member C3,AKR1C3)是一种人类细胞内的多功能酶,广泛表达于肝脏、肺、前列腺、睾丸和乳腺组织等,主要参与类固醇激素的代谢,可以保护人体细胞。然而,近年来一系列的研究发现,AKR1C3在多种肿...醛固酮还原酶(Aldo-keto reductase family 1 member C3,AKR1C3)是一种人类细胞内的多功能酶,广泛表达于肝脏、肺、前列腺、睾丸和乳腺组织等,主要参与类固醇激素的代谢,可以保护人体细胞。然而,近年来一系列的研究发现,AKR1C3在多种肿瘤细胞中呈高表达状态,通过影响血管生成等促进了肿瘤的发生、发展,并且与其不良预后密切相关;此外,AKR1C3还与多种抗肿瘤治疗(包括放疗、化疗和分子靶向治疗等)的耐药有关。深入研究AKR1C3及其抑制剂,以开发新的治疗方法和药物,可能具有重要的科学意义和潜在的实用价值。因此,本文总结和分析了AKR1C3与恶性肿瘤关系的有关研究进展。展开更多
醛酮还原酶1C3(Aldo-Keto Reductase Family 1 Member C3,AKR1C3)是可溶性NADPH还原酶,兼具有3α-羟基类固醇脱氢酶(3α-hydroxysteroid dehydrogenase,3α-HSD)、3β-HSD、17β-HSD和11-酮前列腺素还原酶活性,能催化雌激素、孕酮、雄...醛酮还原酶1C3(Aldo-Keto Reductase Family 1 Member C3,AKR1C3)是可溶性NADPH还原酶,兼具有3α-羟基类固醇脱氢酶(3α-hydroxysteroid dehydrogenase,3α-HSD)、3β-HSD、17β-HSD和11-酮前列腺素还原酶活性,能催化雌激素、孕酮、雄激素和前列腺素代谢。AKR1C3在肿瘤组织中存在异常表达和单核苷酸多态性,与多种激素相关性肿瘤的发生、发展及耐药密切相关。研究显示,AKR1C3能够与雌激素受体(ER)、孕酮受体(PR)、雄激素受体(AR)和过氧化物酶体增殖物激活受体(PPAR)等核受体结合,间接调控这些核受体的反式激活,影响细胞的活性。为了进一步了解AKR1C3对肿瘤发生发展的影响及其与肿瘤耐药的关系,本文对近年与AKR1C3相关肿瘤的研究进行综述。展开更多
Background:Fuzheng Huayu capsule(FZHY)combined with antiviral treatment has been shown to significantly reduce the risk of liver cancer in patients with hepatitis B cirrhosis.However,the potential of FZHY to directly ...Background:Fuzheng Huayu capsule(FZHY)combined with antiviral treatment has been shown to significantly reduce the risk of liver cancer in patients with hepatitis B cirrhosis.However,the potential of FZHY to directly treat liver cancer remains largely unknown.This study aims to investigate the molecular mechanism underlying the potential of FZHY in treating liver cancer.Methods:A network pharmacological analysis was performed using the Traditional Chinese Medicine Systems Pharmacology database to identify FZHY compounds and targets.Disease targets were searched using the Genecards database,and transcriptome data was downloaded from the NCBI database.Gene Ontology analysis was conducted using the DAVID database,and Kyoto Encyclopedia of Genes and Genomes analysis was based on KOBAS and bioinformatics methods.The Swissdock database was used for molecular docking.In cell experiments,the half inhibitory concentration(IC50)of FZHY was determined using the CCK8 method.The effects of FZHY on cell viability,apoptosis,and mitochondrial membrane potential were evaluated using a fluorescence microscope and flow cytometry.The molecular mechanism of FZHY in treating liver cancer was verified using quantitative polymerase chain reaction.Results:A total of 127 compounds and 184 proteins were identified as potential active ingredients and putative liver cancer-related targets.Additionally,1,899 liver cancer targets,279 transcriptome targets,and 3 pathways(p53 signaling pathway,apoptosis and PI3K-Akt pathway)were collected.The FZHY-targets-liver cancer interaction network was constructed.IC50 of FZHY lyophilized powder solution to liver cancer was 5.13 mg/mL(IC50=5.13 mg/mL).FZHY treatment led to an increase in the ratio of cell apoptosis and induced mitochondrial membrane potential damage,resulting in an increase in the number of dead cells.The expression levels of CCNB1 and BIRC5 were induced with FZHY treatment,while the expression levels of AKR1C3 and IGF2 were reduced.Conclusion:FZHY promotes apoptosis of liver cancer cells by acting on the p53 signaling pathway,apoptosis,and PI3K-Akt pathway.CCNB1,BIRC5,AKR1C3,and IGF2 are potential target proteins for FZHY in treating liver cancer.展开更多
目的 探讨AT富交互域3A (ARID3A)对结肠癌细胞化疗敏感性的影响及其作用机制。方法 在人结肠癌细胞系HCT116和SW1116中构建ARID3A过表达或敲低细胞系,设置HCT116-PLVX/SW1116-PLVX过表达对照组、HCT116-ARID3A/SW1116-ARID3A过表达组、H...目的 探讨AT富交互域3A (ARID3A)对结肠癌细胞化疗敏感性的影响及其作用机制。方法 在人结肠癌细胞系HCT116和SW1116中构建ARID3A过表达或敲低细胞系,设置HCT116-PLVX/SW1116-PLVX过表达对照组、HCT116-ARID3A/SW1116-ARID3A过表达组、HCT116-ARID3A-sh1/SW1116-ARID3A-sh1敲减组、HCT116-ARID3A-sh2/SW1116-ARID3A-sh2敲减组和HCT116-SH/SW1116-SH敲减对照组。应用MTT实验检测5-FU作用于各组后的抑制效率。蛋白质谱检测筛选下游调控基因醛酮还原酶家族1成员C3(AKR1C3),采用qRT-PCR和蛋白质印迹法检测ARID3A过表达或敲减对AKR1C3表达的影响。采用双荧光素酶报告基因和染色质免疫沉淀(ChIP)实验分析ARID3A对AKR1C3的调控作用。进一步构建AKR1C3过表达或敲低细胞系,再次应用MTT实验检测其对5-FU的敏感性。结果 与对照组相比,HCT116-ARID3A过表达组(F=151.300,P<0.001;F=11.980,P=0.003;F=5.250,P=0.005)和SW1116-ARID3A过表达组(F=404.902,P<0.001;F=215.901,P<0.001;F=3.185,P=0.023)细胞受5-FU的抑制效率增加,药物和ARID3A表达水平的作用效应存在交互作用。而敲减ARID3A后,相较于对照组细胞表现出了对5-FU敏感性的降低,均P<0.05。进一步筛选出ARID3A的下游靶基因AKR1C3,qRT-PCR实验结果显示,在过表达ARID3A的HCT116和SW1116细胞中,AKR1C3的mRNA水平均低于相应对照组细胞(HCT116:0.395±0.054 vs 1.000±0.162,t=6.147,P=0.004;SW1116:0.250±0.017 vs 1.000±0.332,t=3.911,P=0.017);而在ARID3A敲减细胞中则相反,即AKR1C3的mRNA水平高于相应对照组细胞(HCT116:2.886±0.421 vs 1.000±0.080,t=7.621,P=0.002;SW1116:2.990±0.851 vs 1.000±0.148,t=3.909,P=0.016)。在过表达ARID3A的HCT116和SW1116细胞中,AKR1C3的蛋白水平均低于相应对照组细胞(HCT116:0.780±0.010 vs 1.000±0.012,t=19.630,P=0.004;SW1116:0.130±0.012 vs 0.240±0.029,t=4.880,P=0.032)。而在ARID3A敲减细胞中则相反,即AKR1C3的蛋白水平均高于相应对照组细胞(HCT116:1.630±0.040 vs 1.030±0.026,t=18.140,P=0.005;SW1116:1.070±0.153 vs 0.450±0.033,t=5.590,P=0.031)。并进一步明确ARID3A与AKR1C3结合并发挥其对AKR1C3的转录抑制作用。在HCT116和SW1116细胞中,过表达AKR1C3后,相较于对照组细胞均表现出了对5-FU敏感性的减弱,药物和AKR1C3表达水平的作用效应存在交互作用,均P<0.05。而敲减AKR1C3后,相较于对照组细胞表现出了对5-FU敏感性的增强,均P<0.05。结论 ARID3A通过抑制结肠癌细胞中的耐药相关基因AKR1C3促进结肠癌细胞对化疗药物5-FU的敏感性。展开更多
文摘醛固酮还原酶(Aldo-keto reductase family 1 member C3,AKR1C3)是一种人类细胞内的多功能酶,广泛表达于肝脏、肺、前列腺、睾丸和乳腺组织等,主要参与类固醇激素的代谢,可以保护人体细胞。然而,近年来一系列的研究发现,AKR1C3在多种肿瘤细胞中呈高表达状态,通过影响血管生成等促进了肿瘤的发生、发展,并且与其不良预后密切相关;此外,AKR1C3还与多种抗肿瘤治疗(包括放疗、化疗和分子靶向治疗等)的耐药有关。深入研究AKR1C3及其抑制剂,以开发新的治疗方法和药物,可能具有重要的科学意义和潜在的实用价值。因此,本文总结和分析了AKR1C3与恶性肿瘤关系的有关研究进展。
文摘醛酮还原酶1C3(Aldo-Keto Reductase Family 1 Member C3,AKR1C3)是可溶性NADPH还原酶,兼具有3α-羟基类固醇脱氢酶(3α-hydroxysteroid dehydrogenase,3α-HSD)、3β-HSD、17β-HSD和11-酮前列腺素还原酶活性,能催化雌激素、孕酮、雄激素和前列腺素代谢。AKR1C3在肿瘤组织中存在异常表达和单核苷酸多态性,与多种激素相关性肿瘤的发生、发展及耐药密切相关。研究显示,AKR1C3能够与雌激素受体(ER)、孕酮受体(PR)、雄激素受体(AR)和过氧化物酶体增殖物激活受体(PPAR)等核受体结合,间接调控这些核受体的反式激活,影响细胞的活性。为了进一步了解AKR1C3对肿瘤发生发展的影响及其与肿瘤耐药的关系,本文对近年与AKR1C3相关肿瘤的研究进行综述。
文摘Background:Fuzheng Huayu capsule(FZHY)combined with antiviral treatment has been shown to significantly reduce the risk of liver cancer in patients with hepatitis B cirrhosis.However,the potential of FZHY to directly treat liver cancer remains largely unknown.This study aims to investigate the molecular mechanism underlying the potential of FZHY in treating liver cancer.Methods:A network pharmacological analysis was performed using the Traditional Chinese Medicine Systems Pharmacology database to identify FZHY compounds and targets.Disease targets were searched using the Genecards database,and transcriptome data was downloaded from the NCBI database.Gene Ontology analysis was conducted using the DAVID database,and Kyoto Encyclopedia of Genes and Genomes analysis was based on KOBAS and bioinformatics methods.The Swissdock database was used for molecular docking.In cell experiments,the half inhibitory concentration(IC50)of FZHY was determined using the CCK8 method.The effects of FZHY on cell viability,apoptosis,and mitochondrial membrane potential were evaluated using a fluorescence microscope and flow cytometry.The molecular mechanism of FZHY in treating liver cancer was verified using quantitative polymerase chain reaction.Results:A total of 127 compounds and 184 proteins were identified as potential active ingredients and putative liver cancer-related targets.Additionally,1,899 liver cancer targets,279 transcriptome targets,and 3 pathways(p53 signaling pathway,apoptosis and PI3K-Akt pathway)were collected.The FZHY-targets-liver cancer interaction network was constructed.IC50 of FZHY lyophilized powder solution to liver cancer was 5.13 mg/mL(IC50=5.13 mg/mL).FZHY treatment led to an increase in the ratio of cell apoptosis and induced mitochondrial membrane potential damage,resulting in an increase in the number of dead cells.The expression levels of CCNB1 and BIRC5 were induced with FZHY treatment,while the expression levels of AKR1C3 and IGF2 were reduced.Conclusion:FZHY promotes apoptosis of liver cancer cells by acting on the p53 signaling pathway,apoptosis,and PI3K-Akt pathway.CCNB1,BIRC5,AKR1C3,and IGF2 are potential target proteins for FZHY in treating liver cancer.
文摘目的 探讨AT富交互域3A (ARID3A)对结肠癌细胞化疗敏感性的影响及其作用机制。方法 在人结肠癌细胞系HCT116和SW1116中构建ARID3A过表达或敲低细胞系,设置HCT116-PLVX/SW1116-PLVX过表达对照组、HCT116-ARID3A/SW1116-ARID3A过表达组、HCT116-ARID3A-sh1/SW1116-ARID3A-sh1敲减组、HCT116-ARID3A-sh2/SW1116-ARID3A-sh2敲减组和HCT116-SH/SW1116-SH敲减对照组。应用MTT实验检测5-FU作用于各组后的抑制效率。蛋白质谱检测筛选下游调控基因醛酮还原酶家族1成员C3(AKR1C3),采用qRT-PCR和蛋白质印迹法检测ARID3A过表达或敲减对AKR1C3表达的影响。采用双荧光素酶报告基因和染色质免疫沉淀(ChIP)实验分析ARID3A对AKR1C3的调控作用。进一步构建AKR1C3过表达或敲低细胞系,再次应用MTT实验检测其对5-FU的敏感性。结果 与对照组相比,HCT116-ARID3A过表达组(F=151.300,P<0.001;F=11.980,P=0.003;F=5.250,P=0.005)和SW1116-ARID3A过表达组(F=404.902,P<0.001;F=215.901,P<0.001;F=3.185,P=0.023)细胞受5-FU的抑制效率增加,药物和ARID3A表达水平的作用效应存在交互作用。而敲减ARID3A后,相较于对照组细胞表现出了对5-FU敏感性的降低,均P<0.05。进一步筛选出ARID3A的下游靶基因AKR1C3,qRT-PCR实验结果显示,在过表达ARID3A的HCT116和SW1116细胞中,AKR1C3的mRNA水平均低于相应对照组细胞(HCT116:0.395±0.054 vs 1.000±0.162,t=6.147,P=0.004;SW1116:0.250±0.017 vs 1.000±0.332,t=3.911,P=0.017);而在ARID3A敲减细胞中则相反,即AKR1C3的mRNA水平高于相应对照组细胞(HCT116:2.886±0.421 vs 1.000±0.080,t=7.621,P=0.002;SW1116:2.990±0.851 vs 1.000±0.148,t=3.909,P=0.016)。在过表达ARID3A的HCT116和SW1116细胞中,AKR1C3的蛋白水平均低于相应对照组细胞(HCT116:0.780±0.010 vs 1.000±0.012,t=19.630,P=0.004;SW1116:0.130±0.012 vs 0.240±0.029,t=4.880,P=0.032)。而在ARID3A敲减细胞中则相反,即AKR1C3的蛋白水平均高于相应对照组细胞(HCT116:1.630±0.040 vs 1.030±0.026,t=18.140,P=0.005;SW1116:1.070±0.153 vs 0.450±0.033,t=5.590,P=0.031)。并进一步明确ARID3A与AKR1C3结合并发挥其对AKR1C3的转录抑制作用。在HCT116和SW1116细胞中,过表达AKR1C3后,相较于对照组细胞均表现出了对5-FU敏感性的减弱,药物和AKR1C3表达水平的作用效应存在交互作用,均P<0.05。而敲减AKR1C3后,相较于对照组细胞表现出了对5-FU敏感性的增强,均P<0.05。结论 ARID3A通过抑制结肠癌细胞中的耐药相关基因AKR1C3促进结肠癌细胞对化疗药物5-FU的敏感性。
