title: Kisspeptin regulation of genes involved in cell invasion and angiogenesis in first trimester human trophoblast cells.
abstract: The precise regulation of extravillous trophoblast invasion of the uterine wall is a key process in successful pregnancies. Kisspeptin (KP) has been shown to inhibit cancer cell metastasis and placental trophoblast cell migration. In this study primary cultures of first trimester human trophoblast cells have been utilized in order to study the regulation of invasion and angiogenesis-related genes by KP. Trophoblast cells were isolated from first trimester placenta and their identity was confirmed by immunostaining for cytokeratin-7. Real-time quantitative RT-PCR demonstrated that primary trophoblast cells express higher levels of GPR54 (KP receptor) and KP mRNA than the trophoblast cell line HTR8Svneo. Furthermore, trophoblast cells also expressed higher GPR54 and KP protein levels. Treating primary trophoblast cells with KP induced ERK1/2 phosphorylation, while co-treating the cells with a KP antagonist almost completely blocked the activation of ERK1/2 and demonstrated that KP through its cognate GPR54 receptor can activate ERK1/2 in trophoblast cells. KP reduced the migratory capability of trophoblast cells in a scratch-migration assay. Real-time quantitative RT-PCR demonstrated that KP treatment reduced the expression of matrix metalloproteinase 1, 2, 3, 7, 9, 10, 14 and VEGF-A, and increased the expression of tissue inhibitors of metalloproteinases 1 and 3. These results suggest that KP can inhibit first trimester trophoblast cells invasion via inhibition of cell migration and down regulation of the metalloproteinase system and VEGF-A.
authors.affiliation: MRC/UCT Receptor Biology Unit, Institute for Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Víctor A
authors.initials: VA
authors.lastname: Francis
authors.affiliation: MRC/UCT Receptor Biology Unit, Institute for Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Aron B
authors.initials: AB
authors.lastname: Abera
authors.affiliation: MRC/UCT Receptor Biology Unit, Institute for Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Department of Obstetrics and Gynaecology, Groote Schuur Hospital, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Mushi
authors.initials: M
authors.lastname: Matjila
authors.affiliation: MRC/UCT Receptor Biology Unit, Institute for Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Mammal Research Institute, Zoology and Entomology, University of Pretoria, Pretoria, South Africa; Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.affiliation: MRC/UCT Receptor Biology Unit, Institute for Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Arieh A
authors.initials: AA
authors.lastname: Katz
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D059648:Kisspeptins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D014327:Trophoblasts / Q000187:drug effects* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D042461:Vascular Endothelial Growth Factor A