YAP Is Decreased in Preeclampsia and Regulates Invasion and Apoptosis of HTR-8/SVneo

Abstract

Preeclampsia (PE) is a gestational disorder with hypertension and proteinuria leading to maternal and fetal morbidity and mortality. Yes-associated protein (YAP), a transcription coactivator of Hippo pathway, was identified as an oncoprotein participated in tumorigenesis. However, the effect of YAP on trophoblast has not been investigated. In our study, YAP expression levels in first-trimester, full-term, and PE placentas were detected using quantitative real-time polymerase chain reaction (PCR), Western blot assays, and immunohistochemistry. Yes-associated protein expression was also detected in BeWo and HTR-8/SVneo. Overexpression plasmid and YAP small interfering RNA were introduced into trophoblast cells. Furthermore, we utilized a Transwell invasion assay, flow cytometry, and Cell Counting Kit-8 analysis to examine the role of YAP in the invasion, apoptosis, and proliferation of HTR-8/SVneo trophoblast cells. The result showed that both YAP messenger RNA (mRNA) and protein expression levels were less in preeclamptic placentas. Yes-associated protein mRNA and protein expression levels were more highly expressed in BeWo. Yes-associated protein enhanced cell invasion, reduced the cellular apoptotic response, and had no effect on proliferation. In addition, the overexpression of YAP activated the expression of caudal-related homeobox transcription factor 2 (CDX2), whereas reduced expression of YAP inhibited the expression of CDX2. Our results demonstrate that decreased YAP levels may contribute to the development of PE by regulating trophoblast invasion and apoptosis involving regulation of CDX2. Collectively, we proposed decreased YAP may contribute to trophoblast dysfunction, which suggests it might represent a prognostic biomarker and therapeutic target for PE.

Long non-coding RNA FAM99A modulated YAP1 to affect trophoblast cell behaviors in preeclampsia by sponging miR-134-5p

“…Furthermore, FAM99A positively regulated YAP1 expression by sponging miR-134-5p. Our results are in agreement with those of Sun et al ( 20 ) about the function of YAP1 in PE. These data revealed that FAM99A modulated YAP1 to affect behaviors of trophoblast cells in PE by sponging miR-134-5p.…”

“…Moreover, a recent study indicated that YAP1 regulates LINC00152 to inhibit the progression of colorectal cancer ( 19 ). Sun et al ( 20 ) reported that YAP1 is elevated in PE and facilitates cell metastasis, but impedes apoptosis. However, the underlying mechanism of miR-134-54p and YAP1 is rarely reported in PE.…”

Overexpression of miR-210-3p Impairs Extravillous Trophoblast Functions Associated with Uterine Spiral Artery Remodeling

“…Studies have shown that overexpression of CDX2 in the EVT cell line, HTR8/SVneo, enhances cell invasion through activation of matrix metalloproteinase-9 (MMP9) and inhibition of MMP9 inhibitor, tissue inhibitor metalloproteinase-1 (TIMP1) [25] and that CDX2 expression is regulated by the PI3K/AKT pathway [25]. Additionally, CDX2 is regulated by Yesassociated protein (YAP), which has been shown to promote HTR8/SVneo invasion and reduce apoptosis [26].…”

A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

“…Furthermore, the clinical relevance of the Hippo signaling pathway in human preimplantation development and early human pregnancy is not fully established. Interestingly, YAP1 is expressed in the human placenta and its levels are downregulated in patients with preeclampsia ( Sun et al , 2018 ), indicating that Hippo signaling may be important for human trophoblast lineage development. In support of this notion, a recent study using human cell models revealed that YAP1 and TEAD4 promote self-renewal of cytotrophoblast progenitor cells, while inhibiting formation of differentiated syncytiotrophoblast cells ( Meinhardt et al , 2020 ).…”