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Decrease in Expression of HOXA10 in the Decidua After Embryo Implantation Promotes Trophoblast Invasion.

ABSTRACT: An important step toward successful pregnancy involves invasion of the trophoblast cells into the decidua for placentation. Herein, we show that in the human and baboon decidua HOXA10 expression is downregulated after implantation and that this reduction is most prominent in the decidual cells juxtaposed to the invading placental villi. The supernatants derived from HOXA10-depleted human decidual cells increase the invasiveness of the trophoblast cell lines ACH-3P and JEG3 in vitro; this increase is due to higher expression and activity of matrix metalloproteases (MMPs) and reduced expression of tissue inhibitors of MMPs in both the cell lines. The proinvasive ability of HOXA10-depleted decidual cells is due to increased levels and secretion of leukemia inhibitor factor (LIF) and interleukin (IL)-6. Both these cytokines individually promote invasion of ACH-3P and JEG3 cell by increasing the activities of MMPs and decreasing mRNA levels of TIMPs. Finally, we demonstrate that the supernatants derived from HOXA10-depleted decidual cell-phosphorylated STAT3 (Tyr 705) and knocking down STAT3 in ACH-3P and JEG3 cells restrained the invasion mediated by supernatants derived from HOXA10-depleted decidual cells. These results imply that STAT3 activity is essential and sufficient to promote invasion in response to downregulation of HOXA10 in decidual cells. We propose that downregulation of HOXA10 in the decidual cells promotes the expression of LIF and IL-6, which, in a paracrine manner, activates STAT3 in the trophoblast cells, leading to an increase in MMPs to facilitate invasion.

SUBMITTER: Godbole G

PROVIDER: S-EPMC6283436 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Decrease in Expression of HOXA10 in the Decidua After Embryo Implantation Promotes Trophoblast Invasion.

Godbole Geeta G Suman Pankaj P Malik Ankita A Galvankar Mosami M Joshi Niraj N Fazleabas Asgerally A Gupta Satish Kumar SK Modi Deepak D

Endocrinology 20170801 8

An important step toward successful pregnancy involves invasion of the trophoblast cells into the decidua for placentation. Herein, we show that in the human and baboon decidua HOXA10 expression is downregulated after implantation and that this reduction is most prominent in the decidual cells juxtaposed to the invading placental villi. The supernatants derived from HOXA10-depleted human decidual cells increase the invasiveness of the trophoblast cell lines ACH-3P and JEG3 in vitro; this increas ...[more]

PMID: 28520923

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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

Decrease in Expression of HOXA10 in the Decidua After Embryo Implantation Promotes Trophoblast Invasion.

Publications

Decrease in Expression of HOXA10 in the Decidua After Embryo Implantation Promotes Trophoblast Invasion.

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