Hypoxia and Prostaglandin E Receptor 4 Signalling Pathways Synergise to Promote Endometrial Adenocarcinoma Cell Proliferation and Tumour Growth
Hypoxia and Prostaglandin E Receptor 4 Signalling Pathways Synergise to Promote Endometrial Adenocarcinoma Cell Proliferation and Tumour Growth
复制标题
DOI：
10.1371/journal.pone.0019209
复制
发表时间：
2011-05-12
期刊：
影响因子：
3.7
通讯作者：
Jabbour, Henry N.
中科院分区：
文献类型：
--
作者：
Catalano, Rob D.;Wilson, Martin R.;Jabbour, Henry N.
前列腺素内过氧化物合酶（PTGS）途径通过增强前列腺素（PG）E-2的生物合成和信号传导，是人类肿瘤发展的有力驱动因素。子宫内膜腺癌中PTGS 2的表达和PGE（2）的生物合成增加，然而PTGS和PGE 2调节子宫内膜肿瘤生长的机制尚不清楚。在此，我们研究了（a）与正常子宫内膜相比，子宫内膜腺癌中PGE合酶（PTGES、PTGES-2、PTGES-3）和PGE受体（PTGER 1 -4）的表达谱和（B）PTGER 4在体内子宫内膜肿瘤发生中的作用。我们发现与正常子宫内膜相比，子宫内膜腺癌中PTGES 2和PTGER 4的表达升高，PTGER 1和PTGER 3的表达受到抑制。使用WT石川子宫内膜腺癌细胞和稳定转染有全长PTGER 4 cDNA的石川细胞（PTGER 4细胞）异种移植到裸鼠的背侧，我们表明PTGER 4快速且显著地增强肿瘤生长速率。与增强的PTGER 4介导的肿瘤生长一致，我们发现PTGER 4异种移植物中PTGS 2的表达与WT异种移植物相比升高。此外，我们发现PTGER 4异种移植物的生长速率增加不是由于血管生成增强，而是由增殖指数增加和缺氧调节。在体外，我们发现，PGE 2和缺氧独立诱导PTGER 4的表达，表明两个独立的途径调节前列腺素受体的表达。最后，我们发现PGE 2和缺氧协同促进子宫内膜腺癌细胞的增殖。
The prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG) E-2. PTGS2 expression and PGE(2) 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.