title: CUL1 promotes trophoblast cell invasion at the maternal-fetal interface.
abstract: Human trophoblast progenitor cells differentiate via two distinct pathways, to become the highly invasive extravillous cytotrophoblast (CTB) cells (EVT) or fuse to form syncytiotrophoblast. Inadequate trophoblast differentiation results in poor placenta perfusion, or even complications such as pre-eclampsia (PE). Cullin1 (CUL1), a scaffold protein in cullin-based ubiquitin ligases, plays an important role in early embryonic development. However, the role of CUL1 in trophoblast differentiation during placenta development has not been examined. Here we show that CUL1 was expressed in CTB cells and EVT in the first trimester human placentas by immunohistochemistry. CUL1 siRNA significantly inhibited outgrowth of extravillous explants in vitro, as well as invasion and migration of HTR8/SVneo cells of EVT origin. This inhibition was accompanied by decreased gelatinolytic activities of matrix metalloproteinase (MMP)-9 and increased expression of tissue inhibitors of MMPs (TIMP-1 and -2). Consistently, exogenous CUL1 promoted invasion and migration of HTR8/SVneo cells. Notably, CUL1 was gradually decreased during trophoblast syncytialization and CUL1 siRNA significantly enhanced forskolin-induced fusion of choriocarcinoma BeWo cells. CUL1 protein levels in human pre-eclamptic placental villi were significantly lower as compared to their matched control placentas. Taken together, our results suggest that CUL1 promotes human trophoblast cell invasion and dysregulation of CUL1 expression may be associated with PE.
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors: Q
authors: Q
authors: Zhang
authors: Q
authors: Q
authors: Chen
authors: X
authors: X
authors: Lu
authors: Z
authors: Z
authors: Zhou
authors: H
authors: H
authors: Zhang
authors: H-Y
authors: HY
authors: Lin
authors: E
authors: E
authors: Duan
authors: C
authors: C
authors: Zhu
authors: Y
authors: Y
authors: Tan
authors: H
authors: H
authors: Wang
mesh_terms: D002459:Cell Fusion; D002465:Cell Movement; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000378:metabolism; D005576:Colforsin / Q000378:metabolism; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D034741:RNA, Small Interfering; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D005576:Colforsin; D020780:Matrix Metalloproteinase 9