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Human Chorionic Gonadotropin Produced by the Invasive Trophoblast But Not the Villous Trophoblast Promotes Cell Invasion and Is Down-Regulated by Peroxisome Proliferator-Activated Receptor-

Institut National de la Santé et de la Recherche Médicale Unité 767 (K.H., J.G., V.T., M.G., D.E.-B., T.F.), and Faculté des Sciences Pharmaceutiques et Biologiques (K.H., J.G., V.T., M.G., D.E.-B., T.F.) and Faculté de pharmacie, Génétique Moléculaire (I.L.), Université Paris Descartes, Unité Propre de Recherche de l’Enseignement Superieur Equipe d’Accueil 3618, Université Paris Descartes, Paris F-75006, France; and Assistance Publique-Hôpitaux de Paris (AP-HP) (J.G.), Biologie Hormonale, and AP-HP (V.T.), Maternité Port-Royal, Hôpital Cochin, 75014 Paris, France

Address all correspondence and requests for reprints to: Thierry Fournier, Institut National de la Santé et de la Recherche Médicale, Unité 767, 4 Avenue de l’Observatoire, 75006 Paris, France. E-mail: thierry.fournier{at}univ-paris5.fr.

A critical step in the establishment of human pregnancy is the invasion of the uterus wall by extravillous cytotrophoblasts (EVCTs) during the first trimester. It is well established that human chorionic gonadotropin hormone (hCG) is secreted by the endocrine syncytiotrophoblast (ST) into the maternal compartment. We recently reported that invasive EVCTs also produce hCG, suggesting an autocrine role in the modulation of trophoblast invasion. Here we analyzed the role of hCG secreted in vitro by primary cultures of invasive EVCT and noninvasive ST. We first demonstrated that LH/CG receptor was present in EVCTs in situ and in vitro as well as in an EVCT cell line (HIPEC65). We next showed that hCG secreted by EVCTs stimulated progesterone secretion by MA10 cells in a concentration-dependent manner. Incubation of HIPEC65 with EVCT supernatants induced a 10-fold increase in cell invasion, whereas ST supernatants had no effect. This stimulating effect was strongly decreased when hCG was depleted from EVCT supernatants containing a large amount of the hyperglycosylated form of hCG, which is almost undetectable in ST supernatants. Finally, we investigated the regulation of hCG expression by peroxisome proliferator-activated receptor (PPAR)-, a nuclear receptor shown to inhibit trophoblast invasion. Activation of PPAR decreased - and ß-subunit transcript levels and total hCG secretion in primary EVCTs. Our results offer the first evidence that hCG secreted by the invasive trophoblast, likely the hyperglycosylated form of hCG, but not by the syncytiotrophoblast, promotes trophoblast invasion and may be a PPAR target gene in trophoblast invasion process.

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