Bone morphogenetic protein 2 promotes human trophoblast cell invasion by upregulating N-cadherin via non-canonical SMAD2/3 signaling

Abstract

BMP2 expression is spatiotemporally correlated with embryo implantation and is crucial for endometrial decidualization and fertility in mice. BMP2 has been reported to increase the mesenchymal adhesion molecule N-cadherin and enhance cell invasion in cancer cells; moreover, studies suggest that N-cadherin promotes placental trophoblast invasion. However, whether BMP2 can promote trophoblast cell invasion during placentation remains unknown. The objective of our study was to investigate the effects of BMP2 on human trophoblast cell invasion and the involvement of N-cadherin and SMAD signaling. Primary and immortalized (HTR8/SVneo) cultures of human extravillous trophoblast (EVT) cells were used as study models. Treatment with recombinant human BMP2 increased HTR8/SVneo cell transwell Matrigel invasion as well as N-cadherin mRNA and protein levels, but had no significant effect on cell proliferation. Likewise, BMP2 treatment enhanced primary human EVT cell invasion and N-cadherin production. Basal and BMP2-induced invasion were attenuated by small interfering RNA-mediated downregulation of N-cadherin in both HTR8/SVneo and primary EVT cells. Intriguingly, BMP2 induced the phosphorylation/activation of both canonical SMAD1/5/8 and non-canonical SMAD2/3 signaling in HTR8/SVneo and primary EVT cells. Knockdown of SMAD2/3 or common SMAD4 totally abolished the effects of BMP2 on N-cadherin upregulation in HTR8/SVneo cells. Upregulation of SMAD2/3 phosphorylation and N-cadherin were totally abolished by type I receptor activin receptor-like kinases 2/3 (ALK2/3) inhibitor DMH1; moreover, knockdown of ALK2 or ALK3 inhibited N-cadherin upregulation. Interestingly, activation of SMAD2/3 and upregulation of N-cadherin were partially attenuated by ALK4/5/7 inhibitor SB431542 or knockdown of ALK4, but not ALK5. Our results show that BMP2 promotes trophoblast cell invasion by upregulating N-cadherin via non-canonical ALK2/3/4-SMAD2/3-SMAD4 signaling.

Bone morphogenetic protein 2 promotes human trophoblast cell invasion and endothelial‐like tube formation through ID1‐mediated upregulation of IGF binding protein‐3

“…We have previously shown that BMP2 promotes human trophoblast invasion by upregulating N-cadherin expression and activin A production. 14,15 Here we further demonstrate that ID1 is involved in BMP2-induced trophoblast invasion. However, others have shown that Id1 is downregulated during the differentiation of rat Rcho-1 choriocarcinoma cells into trophoblast giant cells, which are thought to be somewhat equivalent to human EVTs.…”

“…As the biggest subfamily of the TGF‐β superfamily, bone morphogenetic proteins (BMPs) are essential for placental development . Expressed at the maternal‐fetal interface, BMP2 plays essential roles in endometrial decidualization and EVT cell invasion . In addition, embryo implantation promotes endometrium decidualization .…”

“…13 Expressed at the maternal-fetal interface, BMP2 plays essential roles in endometrial decidualization and EVT cell invasion. [14][15][16] In addition, embryo implantation promotes endometrium decidualization. 17,18 BMP2 secreted by endometrial cells and trophoblast cells may mediate their cooperation during placentation in an autocrine/paracrine manner.…”

The role of adiponectin in placentation and preeclampsia

“…egEVTs invade the endometrial glands to facilitate histiotrophic nutrition to the embryo, while evEVTs transform endometrial spiral arteries and decrease their resistance to establish the uteroplacental circulation . The molecules that mediate trophoblast invasion of the decidua are cell adhesion molecules (CAMs) like integrins, cadherins and fibronectin, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). During trophoblast invasion of the decidua, the EVT firstly migrates and degrades the endometrial extracellular matrix with the aid of the MMPs .…”

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

“…BMP2 induces human TB cell invasion by upregulating activin A and inhibin A. BMP2 initiates both canonical SMAD1/5/8 via the ALK3 receptor and non-canonical SMAD2/3 pathways [46]. The same group extended these studies and showed that BMP2 promotes TB cell invasion by upregulating N-cadherin via non-canonical ALK2/3/4-SMAD2/3-SMAD4 signaling [78]. They also revealed the role of BMP2 in promoting TB invasion and tube-like formation by ID1-mediated insulin-like growth factor binding protein-3 (IGFBP3) upregulation in primary and HTR8/SVneo cell cultures [47].…”