Departments of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Panjagutta, Hyderabad, 500082, India.
Mol Biol Rep. 2013 Oct;40(10):5541-50. doi: 10.1007/s11033-013-2655-7. Epub 2013 Aug 24.
Glutamate carboxypeptidase II (GCPII) haplotypes were found to influence susceptibility to prostate cancer. In the current study, we have elucidated the impact of these haplotypes on the expression of PSMA, BNIP3, Ec-SOD, GSTP1 and RASSF1 genes to understand the epigenetic basis of oxidative stress and prostate cancer risk. Expression analysis was carried out by RT-PCR. Bisulphite treated DNA was subjected to MS-PCR and COBRA for epigenetic studies. Plasma MDA and glutathione levels were measured. In prostate cancer, upregulation of BNIP3 (204.4 ± 23.77 vs. 143.9 ± 16.42 %, p = 0.03); and downregulation of Ec-SOD (105.8 ± 13.69 vs. 176.3 ± 21.1 %, p = 0.027) and RASSF1A (16.67 ± 16.0 vs. 90.8 ± 8.5 %, p = 0.0048) was observed. Hypomethylation of BNIP3 (31.25 ± 16.19 vs. 45.70 ± 2.42 %, p < 0.0001), hypermethylation of Ec-SOD (71.4 ± 6.75 vs. 10.0 ± 3.78 %, p < 0.0001) and RASSF1 (76.25 ± 12.53 vs. 30.0 ± 8.82 %, p = 0.0077) was observed in prostate cancer. The gene expression signature of PSMA, BNIP3, Ec-SOD, GSTP1, clearly demarcated cases and controls (AUC = 0.89 in the ROC curve). D191V variant of GCPII showed positive association with oxidative stress and inverse association with Ec-SOD expression. H475Y variant showed positive association with Ec-SOD expression and inverse association with oxidative stress. R190W variant was found to reduce oxidative stress by increasing glutathione levels. GCPII genetic variants contribute to increased oxidative stress and prostate cancer risk by modulating the CpG island methylation of Ec-SOD.
谷氨酸羧肽酶 II（GCPII）单倍型被发现影响前列腺癌的易感性。在目前的研究中，我们已经阐明了这些单倍型对 PSMA、BNIP3、Ec-SOD、GSTP1 和 RASSF1 基因表达的影响，以了解氧化应激和前列腺癌风险的表观遗传基础。表达分析通过 RT-PCR 进行。亚硫酸氢盐处理的 DNA 进行 MS-PCR 和 COBRA 进行表观遗传学研究。测量血浆 MDA 和谷胱甘肽水平。在前列腺癌中，BNIP3 的上调（204.4 ± 23.77 与 143.9 ± 16.42 %，p = 0.03）；Ec-SOD（105.8 ± 13.69 与 176.3 ± 21.1 %，p = 0.027）和 RASSF1A（16.67 ± 16.0 与 90.8 ± 8.5 %，p = 0.0048）的下调。BNIP3 的低甲基化（31.25 ± 16.19 与 45.70 ± 2.42 %，p < 0.0001），Ec-SOD（71.4 ± 6.75 与 10.0 ± 3.78 %，p < 0.0001）和 RASSF1（76.25 ± 12.53 与 30.0 ± 8.82 %，p = 0.0077）在前列腺癌中发生高甲基化。PSMA、BNIP3、Ec-SOD、GSTP1 的基因表达特征清楚地区分了病例和对照（ROC 曲线中的 AUC = 0.89）。GCPII 的 D191V 变体与氧化应激呈正相关，与 Ec-SOD 表达呈负相关。H475Y 变体与 Ec-SOD 表达呈正相关，与氧化应激呈负相关。R190W 变体通过增加谷胱甘肽水平来降低氧化应激。GCPII 遗传变异通过调节 Ec-SOD 的 CpG 岛甲基化，导致氧化应激增加和前列腺癌风险增加。
