title: C19MC microRNAs regulate the migration of human trophoblasts.
abstract: Early in pregnancy, trophoblast invasion into the decidua and inner myometrium is essential for establishment of proper implantation, maternal-fetal exchange, and immunological tolerance of the feto-placental allograft. Unlike villous trophoblasts (VTs), extravillous trophoblasts (EVTs) are unique in their capacity to invade the maternal decidua and myometrium. The largest human microRNA (miRNA) gene cluster, the chromosome 19 miRNA cluster (C19MC), is expressed almost exclusively in the placenta and, rarely, in certain tumors and undifferentiated cells. In the work reported here, we found that the expression of C19MC miRNAs is higher in VTs than in EVTs. Using a bacterial artificial chromosome (BAC)-mediated overexpression of C19MC miRNAs in an EVT-derived cell line, which does not naturally express these miRNAs, we found that C19MC miRNAs selectively attenuate cell migration without affecting cell proliferation or apoptosis. A microarray analysis revealed that C19MC miRNAs regulate target transcripts related to cellular movement. Our data also implicated a specific C19MC member, miR-519d, indirectly regulating the EVT invasive phenotype by targeting CXCL6, NR4A2 and FOXL2 transcripts through a 3'UTR miRNA-responsive element. Together, our data suggest a role for C19MC miRNAs in modulating the migration of EVTs.
authors.affiliation: Magee-Womens Research Institute (L.X., J.-F.M., T.C., W.T.P., E.S., Y.S.), Department of OBGYN and Reproductive Sciences, University of Pittsburgh, Pennsylvania 15213; Medical Systems Biology Research Center (L.X.), Department of Biomedical Engineering, Tsinghua University School of Medicine, Beijing 100084 China; Department of Obstetrics and Fetal-Maternal Medicine (M.K.), Reproductive Biology Unit, Medical University of Vienna, Vienna, A-1090 Austria; and Department of Microbiology and Molecular Genetics (Y.S.), University of Pittsburgh, Pennsylvania 15213.
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Mouillet
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Chu
authors.forename: W Tony
authors.initials: WT
authors.lastname: Parks
authors.forename: Elena
authors.initials: E
authors.lastname: Sadovsky
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
authors.forename: Yoel
authors.initials: Y
authors.lastname: Sadovsky
mesh_terms: D020413:3' Untranslated Regions; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D054427:Chemokine CXCL6 / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D002888:Chromosomes, Human, Pair 19; D010064:Embryo Implantation; D005109:Extracellular Matrix; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D011247:Pregnancy; D014327:Trophoblasts / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; C515503:CXCL6 protein, human; D054427:Chemokine CXCL6; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C546194:MIRN519 microRNA, human; D035683:MicroRNAs; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2