Sales Kurt J, Milne Stuart A, Williams Alistair R W, Anderson Richard A, Jabbour Henry N
Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, University of Edinburgh Academic Center, Edinburgh, United Kingdom EH16 4SB.
J Clin Endocrinol Metab. 2004 Feb;89(2):986-93. doi: 10.1210/jc.2003-031434.
Prostaglandin F(2 alpha)(PGF(2 alpha)) is a bioactive lipid biosynthesized by cyclooxygenase (COX) enzymes and mediates its biological activity via the heptahelical G(q)-coupled PGF(2 alpha)receptor (FP receptor). This study investigated the expression and molecular signaling of the FP receptor in human endometrial adenocarcinomas. Real-time RT-PCR and Western blot analysis confirmed FP receptor expression in endometrial adenocarcinoma of all grades and differentiation. The expression of FP receptor was up-regulated in all endometrial adenocarcinomas compared with normal endometrium. The site of FP receptor expression was localized by in situ hybridization and immunohistochemistry to the neoplastic epithelial cells in all adenocarcinomas. Treatment of endometrial adenocarcinoma explants with PGF(2 alpha) resulted in mobilization of inositol phosphate signaling, indicating functional FP receptor expression. We investigated whether PGF(2 alpha) could trans-activate the epidermal growth factor receptor (EGFR) and trigger the MAPK signaling pathway. Treatment of adenocarcinoma explants and endometrial adenocarcinoma cells (Ishikawa) with PGF(2 alpha)-phosphorylated EGFR, triggered MAPK signaling and enhanced the proliferation of Ishikawa cells. Inactivation of phospholipase C, EGFR kinase, and MAPK kinase with specific inhibitors abolished PGF(2 alpha)-induced trans-activation of EGFR, MAPK signaling, and Ishikawa cell proliferation. These data suggest that PGF(2 alpha)-FP receptor promote endometrial tumorigenesis via a phospholipase C-mediated phosphorylation of the EGFR and MAPK signaling pathways.
前列腺素F（2α）（PGF（2α））是一种由环氧化酶（COX）合成的生物活性脂质，通过七螺旋G（q）偶联的PGF（2α）受体（FP受体）介导其生物学活性。本研究调查了FP受体在人子宫内膜腺癌中的表达及分子信号传导。实时逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹分析证实了FP受体在所有分级和分化程度的子宫内膜腺癌中均有表达。与正常子宫内膜相比，FP受体在所有子宫内膜腺癌中的表达均上调。通过原位杂交和免疫组织化学将FP受体表达部位定位在所有腺癌的肿瘤上皮细胞中。用PGF（2α）处理子宫内膜腺癌外植体导致肌醇磷酸信号传导动员，表明存在功能性FP受体表达。我们研究了PGF（2α）是否能反式激活表皮生长因子受体（EGFR）并触发丝裂原活化蛋白激酶（MAPK）信号通路。用PGF（2α）处理腺癌外植体和子宫内膜腺癌细胞（Ishikawa）可使EGFR磷酸化，触发MAPK信号传导并增强Ishikawa细胞的增殖。用特异性抑制剂使磷脂酶C、EGFR激酶和MAPK激酶失活可消除PGF（2α）诱导的EGFR反式激活、MAPK信号传导和Ishikawa细胞增殖。这些数据表明，PGF（2α）-FP受体通过磷脂酶C介导的EGFR磷酸化和MAPK信号通路促进子宫内膜肿瘤发生。
