Abstract
An appropriate development of the placenta consisting of trophoblast cell migration, invasion, proliferation, and apoptosis, is essential to establishing and maintaining a successful pregnancy. Ubiquitin‐specific protease 2a (USP2a) regulates the processes of metastasis in multiple tumor cells. Yet, no known research has focused on exploring the effect of USP2a on trophoblasts and its possible mechanism in the pathogenies of recurrent miscarriage (RM). In this study, we first detected the decreased mRNA levels and the protein levels of USP2a in placental villous tissue samples from the RM patients. In vitro assays verified that overexpression of USP2a promoted human trophoblast proliferation, migration, invasion, whereas knockdown of USP2a inhibited these processes. Mechanistically, USP2a activated PI3K/Akt/GSK3β signaling pathway to promote nuclear translocation of β‐catenin and further activated epithelial-mesenchymal transition (EMT) in the trophoblasts. Moreover, transforming growth factor-beta (TGF-β) up-regulated USP2a expression in trophoblasts. Interestingly, M2 macrophage secreted TGF-β induced trophoblast migration and invasion, and an anti-TGF-β antibody alleviated this effect. Collectively, this study indicated that USP2a regulated trophoblast invasion and that abnormal USP2a expression might lead to aberrant trophoblast invasion, thus contributing to RM.
Highlights
recurrent miscarriage (RM) is defined by the consecutive loss of two or more clinical pregnancies [1] and affects approximately 2-5% of couples at reproductive age [2]
The relative expression evaluated by western blotting showed similar effects (Figure 6G). These results strongly suggested that M2 macrophage-secreted transforming growth factor-beta (TGF-b) may work together with Ubiquitin‐specific protease 2a (USP2a) as one of the regulators of the biological functions of trophoblasts in patients with RM
It is generally recognized that placental insufficiency is one of the main culprits in RM arising from shallow trophoblast invasion at the initial stages of pregnancy [31, 32]
Summary
RM is defined by the consecutive loss of two or more clinical pregnancies [1] and affects approximately 2-5% of couples at reproductive age [2]. As one of the prerequisites for a successful pregnancy, adequate placentation relies on a delicate chorus between fetal trophoblasts and maternal cells, including proper maternal-fetal crosstalk and trophoblasts development [3]. Deep invasion of placental trophoblast cells into the maternal decidua and myometrium is essential for placental embedment and fetal development. Epithelialmesenchymal transition (EMT), characterized by loss of adhesive epithelial phenotype and USP2a Regulates Trophoblast Invasion acquisition of motile mesenchymal phenotype, has been proven to significantly promote the migration and invasion of extravillous trophoblast cells (EVTs) [4,5,6]. Excessive trophoblast cell apoptosis, along with insufficient trophoblast invasion have all been tightly linked to the development of RM [7]. Exploring trophoblast development is crucial to further understanding RM pathogenesis
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