title: Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways.
abstract: Epidermal growth factor-like domain 7 (Egfl7) is a gene that encodes a partially secreted protein and whose expression is largely restricted to the endothelia. We recently reported that EGFL7 is also expressed by trophoblast cells in mouse and human placentas. Here, we investigated the molecular pathways that are regulated by EGFL7 in trophoblast cells. Stable EGFL7 overexpression in a Jeg3 human choriocarcinoma cell line resulted in significantly increased cell migration and invasiveness, while cell proliferation was unaffected. Analysis of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways showed that EGFL7 promotes Jeg3 cell motility by activating both pathways. We show that EGFL7 activates the epidermal growth factor receptor (EGFR) in Jeg3 cells, resulting in downstream activation of extracellular regulated kinases (ERKs). In addition, we provide evidence that EGFL7-triggered migration of Jeg3 cells involves activation of NOTCH signaling. EGFL7 and NOTCH1 are co-expressed in Jeg3 cells, and blocking of NOTCH activation abrogates enhanced migration of Jeg3 cells overexpressing EGFL7. We also demonstrate that signaling through EGFR and NOTCH converged to mediate EGFL7 effects. Reduction of endogenous EGFL7 expression in Jeg3 cells significantly decreased cell migration. We further confirmed that EGFL7 stimulates cell migration by using primary human first trimester trophoblast (PTB) cells overexpressing EGFL7. In conclusion, our data suggest that in trophoblast cells, EGFL7 regulates cell migration and invasion by activating multiple signaling pathways. Our results provide a possible explanation for the correlation between reduced expression of EGFL7 and inadequate trophoblast invasion observed in placentopathies.
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors: M
authors: M
authors: Massimiani
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors: L
authors: L
authors: Vecchione
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors: D
authors: D
authors: Piccirilli
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors: P
authors: P
authors: Spitalieri
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors: F
authors: F
authors: Amati
authors: Department of Gynecology and Obstetrics, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy.
authors: S
authors: S
authors: Salvi
authors: Department of Gynecology and Obstetrics, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy.
authors: S
authors: S
authors: Ferrazzani
authors: Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, Box 60, New York, NY 10065, USA.
authors: H
authors: H
authors: Stuhlmann
authors: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy campagno@med.uniroma2.it.
authors: L
authors: L
authors: Campagnolo
mesh_terms: D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D066255:EGF Family of Proteins; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010929:Placentation / Q000187:drug effects; D011247:Pregnancy; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1; D011994:Recombinant Proteins; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFL7; MAPK; NOTCH signaling; PI3K; trophoblast migration