Expression of COX-2 and PGE synthase and synthesis of PGE(2)in endometrial adenocarcinoma: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors.
This study was designed to investigate the possible role of cyclo-oxygenase-2 (COX-2) and prostaglandin E(2)(PGE(2)) in endometrial adenocarcinoma. COX-2 RNA expression was confirmed in various grades of adenocarcinoma by ribonuclease protection assay. COX-2 and microsomal glutathione-dependent prostaglandin E synthase (mPGES) expression and PGE(2)synthesis were localised to the neoplastic epithelial cells and endothelial cells. In order to establish whether PGE(2)has an autocrine/paracrine effect in adenocarcinomas, we investigated the expression of 2 subtypes of PGE(2)receptors, namely EP2 and EP4, by real time quantitative PCR. Expression of EP2 and EP4 receptors was detected in adenocarcinomas from all grades of differentiation and was significantly higher than that detected in normal secretory phase endometrium (P< 0.01). The fold induction of expression in adenocarcinoma compared with normal secretory phase endometrium was 28.0 +/- 7.4 and 52.5 +/- 10.1 for EP2 and EP4 receptors respectively. Immunohistochemistry localised the site of expression of EP4 receptor in neoplastic epithelial cells and in the endothelium of carcinomas of all grades of differentiation. Finally, the functionality of the EP2/EP4 receptors was assessed by investigating cAMP generation following in vitro culture of adenocarcinoma tissue in the presence or absence of 300 nM PGE(2). cAMP production in response to PGE(2)was significantly higher in carcinoma tissue than that detected in normal secretory phase endometrium (3.42 +/- 0.46 vs 1.15 +/- 0.05 respectively; P< 0.001). In conclusion, these data suggest that PGE(2)may regulate neoplastic cell function in an autocrine/paracrine manner via the EP2/EP4 receptors.
Jabbour
H N
HN
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh, EH3 9ET, United Kingdom.
Milne
S A
SA
Williams
A R
AR
Anderson
R A
RA
Boddy
S C
SC
D000230:Adenocarcinoma / Q000235:genetics / Q000503:physiopathology*; D000328:Adult; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000032:analysis / Q000096:biosynthesis; D051546:Cyclooxygenase 2; D004273:DNA, Neoplasm / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis*; D016889:Endometrial Neoplasms / Q000235:genetics / Q000503:physiopathology*; D004727:Endothelium; D004847:Epithelial Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis*; D008565:Membrane Proteins; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis*; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D007527:Isoenzymes; D008565:Membrane Proteins; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone