title: Leukemia inhibitory factor regulates differentiation of trophoblastlike BeWo cells through the activation of JAK/STAT and MAPK3/1 MAP kinase-signaling pathways.
abstract: It is well established that syncytium formation involves the fusion of mononucleated trophoblasts into a multinucleated structure and the secretion of hormonal factors, such as human chorionic gonadotropin (hCG). These morphological and biochemical changes are regulated by a plethora of ligands, which upon binding to specific receptors trigger the activation of many signaling pathways, such as janus kinase/signal transducer and activator of transcription (JAK/STAT) and the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinases 1 and 2 (MAPK3/1). We used the forskolin-induced syncytialization of trophoblastlike BeWo cells to characterize at the cellular level the effect mediated by leukemia inhibitory factor (LIF) on trophoblast differentiation and to describe its action at the molecular level. Forskolin induces both hCG secretion and BeWo cell syncytial fusion. Although LIF had no effect on the undifferentiated state of the cells, the cytokine generated a strong reduction in forskolin-induced hCG release. In contrast to its effect on hCG secretion, LIF exerts a synergistic effect toward forskolin-induced fusion. LIF reduced hormonal production through a STAT1- and STAT3-dependent mechanism, whereas MAPK3/1 was not involved in this process. However, both types of signaling molecules were required to mediate the action of LIF in forskolin-induced cell fusion. These data provide novel insights into the regulation of trophoblast cell differentiation by LIF and describe for the first time the molecular mechanism underlying the effect of the cytokine.
authors: Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, Canada.
authors: Katy
authors: K
authors: Leduc
authors: Vincent
authors: V
authors: Bourassa
authors: Eric
authors: E
authors: Asselin
authors: Pierre
authors: P
authors: Leclerc
authors: Julie
authors: J
authors: Lafond
authors: Carlos
authors: C
authors: Reyes-Moreno
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000473:pathology; D005576:Colforsin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000502:physiology; D053614:Janus Kinase 2 / Q000502:physiology; D053612:Janus Kinases / Q000502:physiology*; D053605:Leukemia Inhibitory Factor / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011247:Pregnancy; D050791:STAT Transcription Factors / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018245:Trophoblastic Tumor, Placental Site / Q000473:pathology*; D014594:Uterine Neoplasms / Q000473:pathology
chemical_list: D053605:Leukemia Inhibitory Factor; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D005576:Colforsin; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases