MRP4 regulates ENaC-dependent CREB/COX-2/PGE2 signaling during embryo implantation.

Jun-Jiang Chen,Fei Zou,Ye Chun Ruan,Yan Wang,Hsiao Chang Chan,Xiaojing Meng

doi:10.18632/oncotarget.19676

Abstract

Multi-drug resistance protein 4 (MRP4), a potential chemotherapeutic target as well as a transporter for endogenous signaling molecules (e.g. prostaglandins), is known to be expressed in the endometrium, although its possible role(s) in the physiology of the endometrium remains unknown. Here, we show that MRP4 is upregulated at implantation window and localized to the basolateral membrane of the endometrial epithelium, the interface between the epithelium and stroma in mice. In human endometrial epithelial cells, MRP4 expression is upregulated by ENaC activation and the inhibition of MRP4 blocks ENaC-dependent PGE2 release as well as phosphorylation of CREB. Intrauterine injection of MRP4 inhibitor in mice prior to implantation significantly downregulated implantation markers COX-2, Claudin4 and Lif, and reduced implantation rate. These results in together have revealed a previously undefined role of MRP4 in mediating ENaC-dependent CREB/COX-2/PGE2 signaling essential to embryo implantation with implication in cancer progression as well.

Highlights

Embryo implantation is a prerequisite for a successful pregnancy in mammals [1, 2]
We have previously demonstrated that the epithelial sodium channel (ENaC) in the endometrial epithelial cells can be activated by embryo-derived protease, which subsequently triggers a sequence of events in endometrial epithelial cells, including Ca2+ increase, phosphorylation of CREB (Ca2+/ cAMP responsive element binding protein), downregulation of miR101 and miR199a, upregulation of COX-2 and eventually Prostaglandin E2 (PGE2) production and release to the stroma, leading to decidualization and embryo implantation [10, 11]
Given the reported capacity of Multi-drug resistance protein 4 (MRP4) in transporting PGE2 uniquely among the ATP-binding cassette (ABC) transporters [21], we asked whether MRP4 could mediate the epithelial release of PGE2 triggered by ENaC activation during embryo implantation

Summary

Introduction

Embryo implantation is a prerequisite for a successful pregnancy in mammals [1, 2]. Implantation failure accounts for the majority of pregnancy losses in humans [3] and aberrant implantation is believed to result in severe outcomes at later pregnancy stages including placental insufficiency, preeclampsia and preterm labour [1]. Deletion of enzymes for PGs synthesis including phospholipase A2 and cyclooxygenase-2 (COX2) results in implantation failure in mice [4, 5]. Prostaglandin E2 (PGE2), mainly produced by COX-2-driven synthesis, is considered one of the most important PGs to initiate www.impactjournals.com/oncotarget decidualization [5, 8], an endometrial stromal differentiation process required for embryo implantation [9]. It should be noted that the permeability of plasma membrane to PGE2 is low due to its negative charges [12, 13] and how PGE2 is released from the endometrial epithelial cells for induction of stromal decidualization required for embryo implantation remains unclear

Methods

Results

Conclusion