title: Wnt activation downregulates olfactomedin-1 in Fallopian tubal epithelial cells: a microenvironment predisposed to tubal ectopic pregnancy.
abstract: Ectopic pregnancy (EP) occurs when the embryo fails to transit to the uterus and attach to the luminal epithelium of the Fallopian tube (FT). Tubal EP is a common gynecological emergency and more than 95% of EP occurs in the ampullary region of the FT. In humans, Wnt activation and downregulation of olfactomedin-1 (Olfm-1) occur in the receptive endometrium and coincided with embryo implantation in vivo. Whether similar molecular changes happen in the FT leading to EP remains unclear. We hypothesized that activation of Wnt signaling downregulates Olfm-1 expression predisposes to EP. We investigated the spatiotemporal expression of Olfm-1 in FT from non-pregnant women and women with EP, and used a novel trophoblastic spheroid (embryo surrogate)-FT epithelial cell co-culture model (JAr and OE-E6/E7 cells) to study the role of Olfm-1 on spheroid attachment. Olfm-1 mRNA expression in the ampullary region of non-pregnant FT was higher (P<0.05) in the follicular phase than in the luteal phase. Ampullary tubal Olfm-1 expression was lower in FT from women with EP compared to normal controls at the luteal phase (histological scoring (H-SCORE)=1.3±0.2 vs 2.4±0.5; P<0.05). Treatment of OE-E6/E7 with recombinant Olfm-1 (0.2-5 μg/ml) suppressed spheroid attachment to OE-E6/E7 cells, while activation of Wnt-signaling pathway by Wnt3a or LiCl reduced endogenous Olfm-1 expression and increased spheroid attachment. Conversely, suppression of Olfm-1 expression by RNAi increased spheroid attachment to OE-E6/E7 cells. Taken together, Wnt activation suppresses Olfm-1 expression, and this may predispose a favorable microenvironment of the retained embryo in the FT, leading to EP in humans.
authors.affiliation: Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Suranga P
authors.initials: SP
authors.lastname: Kodithuwakku
authors.forename: Ronald T K
authors.initials: RT
authors.lastname: Pang
authors.forename: Ernest H Y
authors.initials: EH
authors.lastname: Ng
authors.forename: Annie N Y
authors.initials: AN
authors.lastname: Cheung
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Ho
authors.forename: William S B
authors.initials: WS
authors.lastname: Yeung
authors.forename: Kai-Fai
authors.initials: KF
authors.lastname: Lee
mesh_terms: D000328:Adult; D015153:Blotting, Western; D018920:Coculture Techniques; D015536:Down-Regulation / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005187:Fallopian Tubes / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011274:Pregnancy, Tubal / Q000503:physiopathology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D051153:Wnt Proteins; C081451:olfactomedin