Trophoblasts are significant components of the placenta and play crucial roles in maternal-fetal crosstalk. Adequate trophoblast migration and invasion are essential for embryo implantation and healthy pregnancy. Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating enzyme family, regulates the processes of migration and invasion in multiple tumor cells. However, the effects of USP7 on trophoblasts and its possible mechanism in the development of recurrent spontaneous abortion (RSA) are still unclear. In this study, we analyzed the expression of USP7 in villous tissues obtained from RSA patients and healthy controls, and then GNE-6776 (a USP7-specific inhibitor) and USP7 siRNA were used in a trophoblast cell line, HTR-8/SVneo, to further assess the effect of USP7 on the biological function of trophoblasts. Our results provide convincing evidence that USP7 is downregulated in the placental villous tissues of RSA patients. USP7 was found to have a crucial role in the proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) process of trophoblast cells. Further experiments revealed that USP7 directly interacted with the enhancer of zeste homolog 2 (EZH2) and regulated the Wnt/β-catenin signaling pathway in trophoblasts. Taken together, these findings indicate the vital role of USP7 in regulating trophoblast proliferation, migration and invasion, thus affecting the pathogenesis of RSA, providing new insights into the important role of USP7 in the maternal-fetal interface.

Summary Sentence

In conclusion, USP7 prevents recurrent spontaneous abortion by targeting EZH2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/β-catenin pathway.

Graphical Abstract