title: CCN3 regulates proliferation and migration properties in Jeg3 trophoblast cells via ERK1/2, Akt and Notch signalling.
abstract: Previous studies showed that CCN3 is deregulated in early-onset pre-eclampsia (PE), a pregnancy disease associated with impaired trophoblast invasion, which leads to reduced fetal oxygen and nutrition support. Recently, we identified the glycosylated (g-CCN3) and the non-glycosylated (ng-CCN3) form of matricellular CCN3 as key factors in regulation of trophoblast proliferation and invasion. While Jeg3 cells revealed a decreased proliferation upon stimulation with both forms of CCN3, enhanced migration and invasion properties were only found for ng-CCN3. Here, we focused on the signalling cascades mitogen-activated protein kinase (MAPK), PI3 kinase/Akt and Notch/p21 for mediating the dual function of CCN3 on trophoblast proliferation versus migration in Jeg3 cells upon stimulation with g- and ng-recombinant CCN3 (g/ng-rCCN3). Analysis of the CCN3-mediated signalling pathways showed that ng-rCCN3 stimulated migration properties by activating the Akt as well as the MAPK pathway. Moreover, cell migration stimulated by ng-rCCN3 was mediated via Akt and integrin α5β1 but not the antiproliferative effect of CCN3. There was evidence that the Notch pathway might contribute to the antiproliferative properties of both forms of CCN3 by an increase in Notch1 expression and its target gene, the cell cycle inhibitor p21. Our data showed that the presence of both forms of CCN3 is accompanied by a balance of trophoblast proliferation and migration/invasion properties, which are triggered by different signalling pathways. Thus, a deregulated expression of g/ng-CCN3 could lead to an imbalance in proliferation versus invasion, and might contribute to the shallow trophoblast invasion observed in PE.
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wagener
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kazuschke
authors.forename: Elke
authors.initials: E
authors.lastname: Winterhager
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gellhaus
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism
chemical_list: C526319:CCN3 protein, human; D055514:Nephroblastoma Overexpressed Protein; D051880:Receptors, Notch; D051057:Proto-Oncogene Proteins c-akt