TY - JOUR
T1 - Reduced FOXM1 expression limits trophoblast migration and angiogenesis and is associated with preeclampsia.
AU - Monteiro, Lara J.
AU - Cubillos, Sofia
AU - Sanchez, Marianela
AU - Acuña-Gallardo, Stephanie
AU - Venegas, Pía
AU - Herrera, Valentina
AU - Lam, Eric W.F.
AU - Varas-Godoy, Manuel
AU - Illanes, Sebastián E.
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by CONICYT: FONDECYT/POSTDOCTORADO N° 3140038, and FONDECYT REGULAR N° 1140119.
Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by CONICYT: FONDECYT/POSTDOCTORADO N? 3140038, and FONDECYT REGULAR N? 1140119.
Publisher Copyright:
© The Author(s) 2018.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - FOXM1
KW - implantation
KW - placentation
KW - preeclampsia
KW - trophoblast invasion
UR - http://www.scopus.com/inward/record.url?scp=85047925068&partnerID=8YFLogxK
U2 - 10.1177/1933719118778798
DO - 10.1177/1933719118778798
M3 - Article
C2 - 29848205
AN - SCOPUS:85047925068
SN - 1933-7191
VL - 26
SP - 580
EP - 590
JO - Reproductive Sciences
JF - Reproductive Sciences
IS - 5
ER -