title: Leptin-promoted human extravillous trophoblast invasion is MMP14 dependent and requires the cross talk between Notch1 and PI3K/Akt signaling.
abstract: The overexpression of leptin is a crucial feature for the maintenance of pregnancy. The effects of leptin on trophoblast invasion are important to its reproductive function, but the underlying mechanisms remain poorly understood. MMP14 is a member of matrix metalloproteinase (MMP) family that is closely involved in the invasion process. Here, we characterized the importance of MMP14 in the proinvasion effect of leptin on EVT cells and elucidated its molecular mechanisms. Transwell assay revealed that leptin promoted invasion of the immortalized EVT cell line HTR-8/SVneo in a dose- and time-related fashion. Further studies suggested that leptin enhanced HTR-8/SVneo cell invasion by up-regulating MMP14 expression and that knockdown of MMP14 by small interference RNA (siRNA) blocked the proinvasion effect of leptin. Notably, leptin promoted the expression of Notch1 receptor and activated its signaling in HTR-8/SVneo cells, and blocking this pathway by siRNA inhibited both leptin-enhanced MMP14 expression and invasiveness of HTR-8/SVneo cells. Such effects of Notch1 signaling were related with the activation of the PI3K/Akt pathway, which was significantly activated after leptin stimulation and was interfered by Notch1 signaling perturbation. Taken together, our observations suggest that leptin is an effective regulator of MMP14 expression, which consequently plays critical roles in invasion of EVT cells. The promoting effects of leptin on MMP14 require the cross talk between Notch1 and PI3K/Akt signaling pathways.
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Huayang
authors.initials: H
authors.lastname: Wang
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Cheng
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Shao
authors.forename: Zhaogang
authors.initials: Z
authors.lastname: Dong
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Wang
authors.forename: Beihua
authors.initials: B
authors.lastname: Kong
authors.forename: Xun
authors.initials: X
authors.lastname: Qu
mesh_terms: D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D020738:Leptin; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: MMP14; extravillous trophoblasts; invasion; leptin