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Reduced FOXM1 Expression Limits Trophoblast Migration and Angiogenesis and Is Associated With Preeclampsia

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Abstract

Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate in hypoxic conditions and to exhibit analogous vascular, proliferative, migratory, and invasive capacities. Thus, genes that are important for tumorigenesis, such as forkhead box M1 (FOXM1) may also be involved in processes of trophoblast invasion. Indeed, we found Foxm1 protein and messenger RNA (mRNA) levels decreased as gestational age increased in rat’s placentae. Accordingly, when mimicking early placental events in vitro, protein and mRNA expression of FOXM1 increased from 21% to 8% O2, reaching its highest expression at 3% oxygen tension, which reflects early implantation environment, and dropping to very low levels at 1% O2. Remarkably, FOXM1 silencing in JEG-3 cells was able to significantly decrease migration by 27.9%, in comparison with those cells transfected with control siRNA. Moreover, angiogenesis was compromised when conditioned media (CM) from FOXM1-siRNA -JEG-3 (3% O2) was added to human umbilical vein endothelial cells (HUVEC) cells; however, when CM of JEG-3 cells overexpressing FOXM1 at 1% O2 was added, the ability of HUVEC to form tubule networks was restored. Additionally, quantitative real-time polymerase chain reaction (PCR) assays of FOXM1 knockdown and overexpression experiments in JEG-3 cells revealed that the depletion of FOXM1 at 3% O2 and overexpression of FOXM1 at 1% O2 led to downregulation and upregulation of vascular endothelial growth factor transcriptional (VEGF) levels, respectively. Conversely, we also observed deregulation of FOXM1 in placentae derived from pregnancies complicated by preeclampsia (PE). Therefore, we demonstrate that FOXM1 may be a new regulatory protein of early placentation processes and that under chronic hypoxic conditions (1% O2) and in patients with severe PE, its levels decrease.

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Authors and Affiliations

  1. Laboratory of Reproductive Biology, Centre for Biomedical Research, Faculty of Medicine, Universidad de los Andes, Av. Plaza 2501, Las Condes, Santiago, 7620001, Chile

    Lara J. Monteiro MSc, PhD, Sofia Cubillos BSc, Marianela Sanchez BSc, Stephanie Acuña-Gallardo BSc, Pía Venegas BSc, Valentina Herrera BSc, Manuel Varas-Godoy BSc, PhD & Sebastián E. Illanes MD, MSc

  2. Department of Maternal-Foetal Medicine, Clínica Dávila, Santiago, Chile

    Pía Venegas BSc & Sebastián E. Illanes MD, MSc

  3. Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, Hammersmith Hospital Campus, London, United Kingdom

    Eric W.-F. Lam BSc, PhD, MBA

Authors
  1. Lara J. Monteiro MSc, PhD
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  2. Sofia Cubillos BSc
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  3. Marianela Sanchez BSc
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  4. Stephanie Acuña-Gallardo BSc
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  5. Pía Venegas BSc
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  6. Valentina Herrera BSc
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  7. Eric W.-F. Lam BSc, PhD, MBA
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  8. Manuel Varas-Godoy BSc, PhD
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  9. Sebastián E. Illanes MD, MSc
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Correspondence to Lara J. Monteiro MSc, PhD.

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Authors’ Note

The work of this manuscript was carried out at the Universidad de los Andes, Chile.

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Monteiro, L.J., Cubillos, S., Sanchez, M. et al. Reduced FOXM1 Expression Limits Trophoblast Migration and Angiogenesis and Is Associated With Preeclampsia. Reprod. Sci. 26, 580–590 (2019). https://doi.org/10.1177/1933719118778798

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