title: Regulation of miR-101/miR-199a-3p by the epithelial sodium channel during embryo implantation: involvement of CREB phosphorylation.
abstract: In our previous study, we have demonstrated that the epithelial sodium channel (ENaC) mediates the embryo-derived signals leading to the activation of CREB and upregulation of cyclooxygenase type 2 (COX2) required for embryo implantation. This study aims to investigate whether microRNAs (miRNAs) are involved in the ENaC-induced upregulation of COX2 during embryo implantation. The results show that the levels of miR-101 and miR-199a-3p, two COX2 targeting miRNAs, are reduced by ENaC activation, and increased by ENaC inhibition or knock-down of ENaC subunit (ENaCα) in human endometrial surface epithelial (HES) cells or in mouse uteri during implantation. Phosphorylation of CREB is induced by the activation of ENaC, and blocked by ENaC inhibition or knockdown in HES cells. Knockdown of ENaCα or CREB in HES cells or in mouse uterus in vivo results in increases in miR-101 and miR-199a-3p, accompanied with decreases in COX2 protein levels and reduction in implantation rate. The downregulation of COX2 caused by knockdown of ENaC or CREB can be recovered by the inhibitors of miR-101 or miR-199a-3p in HES cells. These results reveal a novel molecular mechanism modulating COX2 expression during embryo implantation via ENaC-dependent CREB activation and COX2-targeting miRNAs.
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Xiao
authors.initials: X
authors.lastname: Sun
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Ye Chun
authors.initials: YC
authors.lastname: Ruan
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Guo
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Epithelial Cell Biology Research CenterKey Laboratory for Regenerative Medicine of Ministry of Education of China, Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong hsiaocchan@cuhk.edu.hk.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000502:physiology; D010064:Embryo Implantation / Q000502:physiology*; D004622:Embryo, Mammalian / Q000502:physiology; D004717:Endometrium / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology; D053503:Epithelial Sodium Channels / Q000502:physiology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000502:physiology*; D023421:Models, Animal; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D053503:Epithelial Sodium Channels; C534072:MIRN101 microRNA, human; C581233:MIRN101 microRNA, mouse; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D034741:RNA, Small Interfering; C531408:mirn199 microRNA, human; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2