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H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating T?R3 in placentae with fetal growth restriction.

ABSTRACT: Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-? receptor (T?R3) following H19 knockdown. Decreased T?R3 expression is also seen in FGR placentae. T?R3 repression decreases EVT cell migration and invasion, owing to impaired TGF-? signaling through a non-canonical TGF-? signaling pathway. Further, we identify T?R3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/T?R3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR.

SUBMITTER: Zuckerwise L

PROVIDER: S-EPMC5122399 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction.

Zuckerwise Lisa L Li Jing J Lu Lingeng L Men Yi Y Geng Tingting T Buhimschi Catalin S CS Buhimschi Irina A IA Bukowski Radek R Guller Seth S Paidas Michael M Huang Yingqun Y

Oncotarget 20160601 25

Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome ...[more]

PMID: 27223264

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Project description:Successful implantation requires coordinated migration and invasion of trophoblast cells into a receptive endometrium. Reduced forkhead box M1 (FOXM1) expression limits trophoblast migration and angiogenesis in choriocarcinoma cell lines, and in a rat model, placental FOXM1 protein expression was significantly upregulated in the early stages of pregnancy compared to term pregnancy. However, the precise role of FOXM1 in implantation events remains unknown. By analyzing mice blastocysts at embryonic day (E3.5), we have demonstrated that FOXM1 is expressed as early as the blastocyst stage, and it is expressed in the trophectoderm of the blastocyst. Since controlled oxygen tension is determinant for achieving normal implantation and placentation and a chronic hypoxic environment leads to shallow trophoblast invasion, we evaluated if FOXM1 expression changes in response to different oxygen tensions in the HTR-8/SVneo first trimester human trophoblast cell line and observed that FOXM1 expression was significantly higher when trophoblast cells were cultured at 3% O2, which coincides with oxygen concentrations in the uteroplacental interface at the time of implantation. Conversely, FOXM1 expression diminished in response to 1% O2 that resembles a hypoxic environment in utero. Migration and angiogenesis were assessed following FOXM1 knockdown and overexpression at 3% O2 and 1% O2, respectively, in HTR-8/SVneo cells. FOXM1 overexpression increased transmigration ability and tubule formation. Using a 3D trophoblast invasion model with trophospheres from HTR-8/SVneo cells cultured on a layer of MATRIGEL and of mesenchymal stem cells isolated from menstrual fluid, we observed that trophospheres obtained from 3D trophoblast invasion displayed higher FOXM1 expression compared with pre-invasion trophospheres. Moreover, we have also observed that FOXM1-overexpressing trophospheres increased trophoblast invasion compared with controls. HTR-8/SVneo-FOXM1-depleted cells led to a downregulation of PLK4, VEGF, and MMP2 mRNA expression. Our current findings suggest that FOXM1 participates in embryo implantation by contributing to trophoblast migration and early trophoblast invasion, by inducing transcription activation of genes involved in these processes. Maternal-fetal communication is crucial for trophoblast invasion, and maternal stromal cells may induce higher levels of FOXM1 in trophoblast cells.

Dataset Information

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating T?R3 in placentae with fetal growth restriction.

Publications

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction.

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