Prostaglandin E2 Induces Fibroblast Growth Factor 9 via EP3-Dependent Protein Kinase Cδ and Elk-1 Signaling

Abstract

Fibroblast growth factor 9 (FGF-9) is a potent mitogen that controls the proper development of many tissues and organs. In contrast, aberrant expression of FGF-9 also results in the evolution of many human diseases, such as cancers and endometriosis. Despite its vital function being reported, the cellular and molecular mechanisms responsible for the regulation of FGF-9 expression are mostly unknown. We report here that prostaglandin E₂ (PGE₂) induces expression of FGF-9, which promotes endometriotic stromal cell proliferation, through the EP3 receptor-activated protein kinase Cδ (PKCδ) signaling pathway. Activation of PKCδ leads to phosphorylation of ERK1/2, and the transcription factor Elk-1 thereby promotes transcription of FGF-9. Two Elk-1 cis-binding sites located at nucleotides −1324 to −1329 and −1046 to −1051 of the human FGF-9 promoter are identified as crucial for mediating PGE₂ actions. Collectively, we demonstrate, for the first time, that PGE₂ can directly induce FGF-9 expression via a novel signaling pathway involving EP3, PKCδ, and a member of the ETS domain-containing transcription factor superfamily in primary human endometriotic stromal cells. Our findings may also provide a molecular framework for considering roles for PGE₂ in FGF-9-related embryonic development and/or human diseases.