Prostaglandin E 2 Induces FGF‐9 Expression in Human Endometriotic Stromal Cells

Abstract

Fibroblast Growth Factor-9 (FGF-9) is a mitogen and survival factor for nerve and mesenchymal cells. Previously, we reported that FGF-9 and its high affinity receptors were induced by estrogen (E2) in the endometriotic lesion. Since prostaglandin E2 (PGE2) is a potent inducer for E2 production and the expression of FGF-9 is E2-dependent, we sought to determine roles of PGE2 in the regulation of FGF-9 in endometriotic stromal cells. Administration of PGE2 markedly increased FGF-9 mRNA expression, which was not inhibited by pretreatment with ER antagonist, ICI182,870, indicating an E2-independent pathway may be existed. Treatment of the cells with PGE2 enhanced FGF-9 mRNA expression which was blocked by pre-treatment with MEK inhibitor, PKC inhibitor, or calcium/calmodulin dependent kinase inhibitor but not by the PKA inhibitor or PI3 kinase inhibitor. PGE2 caused rapid and transient elevation of intracellular Ca2+ concentration, phosphorylation of PKC α/β II, PKC δ, PKC γ, and ERK1/2 in endometriotic stromal cell. Transient transfection with si_PKCδ or dominant negative ERK1/2 blocked the induction of FGF-9 expression mediated by PGE2. Further study demonstrated that EP3 agonist, sulprostone, exerted similar inductive effect as that by PGE2. These data indicated that PGE2 directly regulates FGF9 gene expression via EP3-mediated signaling pathway, which is parallel to PGE2-indued E2 production in human endometriotic stromal cell.