{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:24:27Z","timestamp":1784042667254,"version":"3.55.0"},"reference-count":51,"publisher":"S. Karger AG","issue":"3-4","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gynecol Obstet Invest"],"published-print":{"date-parts":[[2022]]},"abstract":"<b><i>Objectives:<\/i><\/b> Hypoxia is a common feature of extravillous trophoblast (EVT) cells that promote invasion during the early stages of human placentation. This study aimed to examine whether hypoxia-induced an invasive phenotype in EVT cells in vitro and explore the underlying molecular mechanisms. <b><i>Design:<\/i><\/b> The invasiveness of primary EVT cells isolated from the first trimester placental tissues during weeks 5\u20138 of gestation was examined under hypoxic (5% O<sub>2<\/sub>) and normoxic (20% O<sub>2<\/sub>) conditions. <b><i>Methods:<\/i><\/b> Invasiveness was determined by transwell and wound-healing invasion assays using the IncuCyte ZOOM\u2122 Live-Cell Imaging System. Protein expression of the urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor of hypoxia or normoxia-treated cells was measured using Western blot analysis. Knockdown of hypoxia-inducible factor-1 alpha (HIF-1\u03b1) was assessed using small interfering RNA (siRNA). <b><i>Results:<\/i><\/b> Hypoxia enhanced EVT cell invasion but did not affect apoptosis. The stimulatory effect of hypoxia on EVT cell invasiveness was associated with induction of the uPA-uPAR pathway. The synthetic inhibitor of uPAR significantly inhibited hypoxia-induced EVT cell invasion. Silencing of HIF-1\u03b1 by siRNA abolished the stimulatory effect of hypoxia and inhibited the upregulation of uPAR expression, suggesting that the HIF-1\u03b1-uPAR signal is the key mediator for hypoxia-induced EVT cell invasion. Further experiments need to be performed to elucidate the HIF-1\u03b1-uPAR signal pathways. <b><i>Conclusions:<\/i><\/b> The low oxygen-regulated early events of EVT invasion may be mediated by the HIF-1\u03b1-uPAR pathway. <\/jats:p>","DOI":"10.1159\/000525851","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T21:00:38Z","timestamp":1656968438000},"page":"232-241","source":"Crossref","is-referenced-by-count":17,"title":["Hypoxia Promotes Extravillous Trophoblast Cell Invasion through the Hypoxia-Inducible Factor Urokinase-Type Plasminogen Activator Receptor Pathway"],"prefix":"10.1159","volume":"87","author":[{"given":"Aiko","family":"Shigemitsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6129-5074","authenticated-orcid":false,"given":"Katsuhiko","family":"Naruse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8124-6269","authenticated-orcid":false,"given":"Hiroshi","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2022,7,4]]},"reference":[{"key":"ref1"},{"key":"ref2"},{"key":"ref3"},{"key":"ref4"},{"key":"ref5"},{"key":"ref6"},{"key":"ref7"},{"key":"ref8"},{"key":"ref9"},{"key":"ref10"},{"key":"ref11"},{"key":"ref12"},{"key":"ref13"},{"key":"ref14"},{"key":"ref15"},{"key":"ref16"},{"key":"ref17"},{"key":"ref18"},{"key":"ref19"},{"key":"ref20"},{"key":"ref21"},{"key":"ref22"},{"key":"ref23"},{"key":"ref24"},{"key":"ref25"},{"key":"ref26"},{"key":"ref27"},{"key":"ref28"},{"key":"ref29"},{"key":"ref30"},{"key":"ref31"},{"key":"ref32"},{"key":"ref33"},{"key":"ref34"},{"key":"ref35"},{"key":"ref36"},{"key":"ref37"},{"key":"ref38"},{"key":"ref39"},{"key":"ref40"},{"key":"ref41"},{"key":"ref42"},{"key":"ref43"},{"key":"ref44"},{"key":"ref45"},{"key":"ref46"},{"key":"ref47"},{"key":"ref48"},{"key":"ref49"},{"key":"ref50"},{"key":"ref51"}],"container-title":["Gynecologic and Obstetric Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/525851","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/525851","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T15:10:05Z","timestamp":1745421005000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000525851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022]]},"references-count":51,"journal-issue":{"issue":"3-4","published-online":{"date-parts":[[2022,10,6]]},"published-print":{"date-parts":[[2022,10,11]]}},"URL":"https:\/\/doi.org\/10.1159\/000525851","archive":["Portico"],"relation":{},"ISSN":["0378-7346","1423-002X"],"issn-type":[{"value":"0378-7346","type":"print"},{"value":"1423-002X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022]]}}}