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

// Jun-Jiang Chen 1, 2 , Yan Wang 2 , Xiaojing Meng 1 , Ye Chun Ruan 2, 4, 5 , Fei Zou 1 and Hsiao Chang Chan 2, 3, 4 1 Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China 2 Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China 3 Sichuan University – The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, China 4 Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China 5 Interdisciplinary Division of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China Correspondence to: Hsiao Chang Chan, email: hsiaocchan@cuhk.edu.hk Fei Zou, email: zoufei616@163.com Ye Chun Ruan, email: sharon.yc.ruan@polyu.edu.hk Keywords: MRP4, embryo implantation, CREB, COX-2, PGE 2 Received: April 28, 2017      Accepted: May 22, 2017      Published: July 28, 2017 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 PGE 2 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/PGE 2 signaling essential to embryo implantation with implication in cancer progression as well.