Abstract
The prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG) E2. PTGS2 expression and PGE2 biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE2 regulate endometrial tumour growth is unknown. Here we investigated (a) the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3) and PGE receptors (PTGER1–4) in endometrial adenocarcinomas compared with normal endometrium and (b) the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells) xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE2 and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE2 and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells.
Highlights
Endometrioid adenocarcinoma arising from the endometrial glandular epithelium is one of the leading causes of cancer-related morbidity in women world-wide [1,2]
We undertook a comprehensive analysis of the expression profile of the PGE synthase enzymes (PTGES, -2, -3) and E-series prostanoid receptors (PTGER1–4) in endometrial adenocarcinoma by quantitative RT-polymerase chain reaction (PCR) analysis (Figure 1 and Figure S1)
We found elevated expression of PTGES2 (P,0.01) and PTGER4 (P,0.01) in all grades of endometrial adenocarcinomas compared with pooled normal endometrium
Summary
Endometrioid adenocarcinoma arising from the endometrial glandular epithelium is one of the leading causes of cancer-related morbidity in women world-wide [1,2]. One of the most common mutations in endometrial adenocarcinomas is located in the dual specificity phosphatase PTEN (phosphatase and tensin homologue deleted from chromosome ten) gene [2]. Animal models in which PTEN expression is inactivated in the endometrium have shown that loss of the PTEN function rapidly and unfailingly induces endometrial cancer [4]. Inactivation of PTEN function promotes protein kinase B ( called Akt) activation which in turn stimulates the activity of several target genes involved in cell proliferation [5]. One the major targets of Akt signalling in endometrial adenocarcinoma cells, is prostaglandin endoperoxide synthase (PTGS) 2 ( called cyclooxygenase 2) [4,6]
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