title: Activator protein-2 impairs the invasion of a human extravillous trophoblast cell line.
abstract: The reduced migration/invasion of extravillous trophoblasts (EVTs) is a key feature of the genesis of preeclampsia. We and others previously reported that transcriptional factors activator protein-2 (AP-2) alpha and AP-2gamma act as suppressors of tumor invasion. The present study examined the expressions of AP-2alpha and AP-2gamma in preeclamptic placenta vs. control placenta and investigated their effect on the function of EVTs. The expressions of AP-2alpha and AP-2gamma were elevated in the preeclamptic placentas in comparison with the gestational age-matched control placentas. Their expressions also increased in EVTs of the preeclamptic placentas. Thereafter, we transfected AP-2alpha or AP-2gamma into human EVT cell line, HTR-8/SVneo. The overexpression of AP-2alpha or AP-2gamma decreased the migratory and invasive abilities in HTR-8/SVneo cells. This was followed by the reduction of protease activated receptor-1 and matrix metalloproteinases and a significant induction of plasminogen activator inhibitor-1 and the tissue inhibitor of metalloproteinase-1. AP-2alpha and AP-2gamma were weakly expressed in the cultured EVTs and HTR-8/SVneo cells, whereas they were induced by TNF-alpha, which increases in preeclamptic placenta and impairs trophoblast invasion. In the presence of TNF-alpha, the invasion of the HTR-8/SVneo cells was partially restored by a blocking of AP-2 induction using small interfering RNA of AP-2. The present data suggest that AP-2 may suppress trophoblast migration and invasion, thus leading to a shallow placentation in preeclampsia.
authors.affiliation: Department of Maternal and Perinatal Medicine, Nagoya Graduate University School of Medicine, Nagoya 466-8550, Japan. itoto@med.nagoya-u.ac.jp
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kotani
authors.forename: Akira
authors.initials: A
authors.lastname: Iwase
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ino
authors.forename: Seiji
authors.initials: S
authors.lastname: Sumigama
authors.forename: Eiko
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Atsuo
authors.initials: A
authors.lastname: Itakura
authors.forename: Seiji
authors.initials: S
authors.lastname: Nomura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D044463:Receptor, PAR-1 / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000502:physiology*; D014327:Trophoblasts / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D044463:Receptor, PAR-1; D019715:Tissue Inhibitor of Metalloproteinase-1; D050656:Transcription Factor AP-2; D014409:Tumor Necrosis Factor-alpha