| 629006608 | Clinical significance of aberrant methylation of prostaglandin E receptor 2 (PTGER2) in nonsmall cell lung cancer: association with prognosis, PTGER2 expression, and epidermal growth factor receptor mutation. | Tian L, etal., Cancer. 2008 Sep 15;113(6):1396-403. doi: 10.1002/cncr.23694. |
BACKGROUND: The expression of prostaglandin E receptor 2 (PTGER2) affects the biologic behavior of various types of malignant tumors. Recently, transactivation of both PTGER2 and epidermal growth factor receptor (EGFR) has been reported in some tumors.
METHODS: PTGER2 gene expression and possible aberrant methylation of the PTGER2 gene were investigated in 10 nonsmall cell lung cancer (NSCLC) cell lines, 233 primary tumors, and 168 adjacent nonmalignant lung tissues. They were analyzed with reference to an association with EGFR mutation in 133 clinical lung adenocarcinomas and were correlated with patient survival.
RESULTS: Down-regulation of PTGER2 expression was observed in 8 of 10 NSCLC cell lines. Demethylation of 5 expression-negative cell lines restored the expression of PTGER2. Aberrant methylation of the PTGER2 gene was reversely concordant with its messenger RNA expression. PTGER2 methylation was detected in 137 of 233 NSCLC specimens (58%) but was detected in only 2 of 168 nonmalignant lung tissues (1%). Both NSCLCs and adenocarcinomas that had PTGER2 methylation predicted a significantly better prognosis than those without PTGER2 methylation (P = .0051 and P = .0171, respectively). PTGER2 methylation was present with greater frequency in tumors with EGFR mutation than in non-EGFR mutated tumors (P = .0095), and the significance of the correlation was independent after adjusting for sex and smoking status (P = .0144).
CONCLUSIONS: Aberrant methylation of the PTGER2 gene was observed frequently in NSCLC tissues and was associated with the presence of EGFR mutation and a better prognosis. | 18666211 | 2008-09-15 |
| 629006540 | Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. | Huang SK, etal., Am J Pathol. 2010 Nov;177(5):2245-55. doi: 10.2353/ajpath.2010.100446. Epub 2010 Oct 1. | Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that is characterized by excessive proliferation of fibroblasts. The lipid mediator prostaglandin E2 (PGE2) has the capacity to limit fibrosis through its inhibition of numerous functions of these fibroblasts; however, in the setting of fibrosis, fibroblasts have been shown to be resistant to PGE2. We have linked such resistance to decreased expression levels of the E prostanoid 2 (EP2) receptor. In this study, in fibroblasts from both mice and humans with pulmonary fibrosis, we show that DNA hypermethylation is responsible for diminished EP2 expression levels and PGE2 resistance. Bisulfite sequencing of the prostaglandin E receptor 2 gene (PTGER2) promoter revealed that fibrotic fibroblasts exhibit greater PTGER2 methylation than nonfibrotic control cells. Treatment with the DNA methylation inhibitors 5-aza-2'-deoxycytidine and zebularine as well as DNA methyltransferase-specific siRNA decreased PTGER2 methylation, increased EP2 mRNA and protein expression levels, and restored PGE2 responsiveness in fibrotic fibroblasts but not in nonfibrotic controls. PTGER2 promoter hypermethylation was driven by an increase in Akt signal transduction. In addition to results described for the PTGER2 promoter, fibrotic fibroblasts also exhibited increased global DNA methylation. These findings demonstrate that the down-regulation of PTGER2 and consequent PGE2 resistance are both mediated by DNA hypermethylation; we identified increased Akt signal transduction as a novel mechanism that promotes DNA hypermethylation during fibrogenesis. | 20889571 | 2010-11-01 |
| 629006543 | Polymorphisms rs2745557 in PTGS2 and rs2075797 in PTGER2 are associated with the risk of chronic obstructive pulmonary disease development in a Tunisian cohort. | Mani S, etal., Prostaglandins Leukot Essent Fatty Acids. 2021 Mar;166:102252. doi: 10.1016/j.plefa.2021.102252. Epub 2021 Jan 28. | We hypothesized that polymorphisms of genes involved in the prostaglandin pathway could be associated with COPD. In this study we explored the involvement of genetic polymorphisms in PTGS2, PTGER2 and PTGER4 genes in the development and severity of COPD and thei r effects on plasma concentrations of inflammatory/oxidative stress markers. We identified genotypes of PTGS2, PTGER2 and PTGER4 SNPs in a Tunisian cohort including COPD patients (n = 138) and control subjects (n = 216) using PCR-RFLP and PCR TaqMan. Pulmonary function (FEV1 and FVC) were assessed by plethsmography. PGE2, PGD2 and cytokine plasma (IL-6, IL-18, TNF-α, TGF-β) concentrations were measured using ELISA and colorimetric standard methods were used to determine oxidative stress concentrations. Genotype frequencies of rs2745557 in PTGS2 and rs2075797 in PTGER2 were different between COPD cases and controls. There was no correlation between these polymorphisms and lung function parameters. For rs2745557, the A allele frequency was higher in COPD cases than in controls. For rs2075797, carriers of the GG genotype were more frequent in the COPD group than in controls. Only rs2745557 in PTGS2 had an effect on PGD2 and cytokine plasma concentrations. PGD2 was significantly decreased in COPD patients with the GA or AA genotypes. In contrast, IL-18 and NO plasma concentrations were increased in COPD rs2745557 A allele carriers as compared to homozygous GG subjects. Our findings suggest that rs2745557 in PTGS2 and rs2075797 in PTGER2 are associated with COPD development but not with its severity. | 33545665 | 2021-03-01 |
