title: CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties.
abstract: During placental development, continuous invasion of trophoblasts into the maternal compartment depends on the support of proliferating extravillous trophoblasts (EVTs). Unlike tumor cells, EVTs escape from the cell cycle before invasion into the decidua and spiral arteries. This study focused on the regulation properties of glycosylated and non-glycosylated matricellular CCN1 and CCN3, primarily for proliferation control in the benign SGHPL-5 trophoblast cell line, which originates from the first-trimester placenta. Treating SGHPL-5 trophoblast cells with the glycosylated forms of recombinant CCN1 and CCN3 decreased cell proliferation by bringing about G0/G1 cell cycle arrest, which was accompanied by the upregulation of activated Notch-1 and its target gene p21. Interestingly, both CCN proteins increased senescence-associated β-galactosidase activity and the expression of the senescence marker p16. The migration capability of SGHPL-5 cells was mostly enhanced in response to CCN1 and CCN3, by the activation of FAK and Akt kinase but not by the activation of ERK1/2. In summary, both CCN proteins play a key role in regulating trophoblast cell differentiation by inducing senescence and enhancing migration properties. Reduced levels of CCN1 and CCN3, as found in early-onset preeclampsia, could contribute to a shift from invasive to proliferative EVTs and may explain their shallow invasion properties in this disease.
authors.affiliation: a Department of Molecular Biology , University of Duisburg-Essen , Essen , Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Kipkeew
authors.affiliation: b Department of Gynecology and Obstetrics , University of Duisburg-Essen , Essen , Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Kirsch
authors.affiliation: c Institute of Cell Biology, University of Duisburg-Essen , Essen , Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
authors.affiliation: d Department of Developmental Biology , University of Duisburg-Essen , Essen , Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Wuelling
authors.affiliation: a Department of Molecular Biology , University of Duisburg-Essen , Essen , Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Winterhager
authors.affiliation: a Department of Molecular Biology , University of Duisburg-Essen , Essen , Germany.|b Department of Gynecology and Obstetrics , University of Duisburg-Essen , Essen , Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gellhaus
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D055515:Cysteine-Rich Protein 61; D055514:Nephroblastoma Overexpressed Protein; D051880:Receptors, Notch; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D001616:beta-Galactosidase
keywords: CCN1; CCN3; migration; placenta; senescence; trophoblast