Downregulation of CCNA2 disturbs trophoblast migration, proliferation, and apoptosis during the pathogenesis of recurrent miscarriage.

Abstract

Recurrent miscarriage (RM) is defined as two or more pregnancy losses until 24weeks of gestation, which distresses up to 1-5% of couples worldwide. Cyclin A2 (CCNA2) regulates the cell cycle by promoting transition through G1/S and G2/M. Little is known about CCNA2's functions in trophoblast, although it is highly expressed in the placenta. We therefore sought to explore the role of CCNA2 in RM and early pregnancy. First-trimester human placental tissues were collected from patients with RM and normal pregnant women to clarify the expression level of CCNA2. First-trimester human villi explants culture was performed as an ex vivo model to study the functions of CCNA2. The HTR8/SVneo cells were studied for in vitro experiments. The migration, proliferation, and apoptosis levels of trophoblast were examined in the CCNA2-knockdown and CCNA2-overexpressing HTR8 cells. Results Our study revealed that CCNA2 was downregulated in trophoblast of RM first-trimester villi. Results showed that CCNA2 promotes migration of HTR8 cells via the RhoA-ROCK signaling and that CCNA2 increased HTR8 proliferation and inhibited their apoptosis via p53 pathway. In addition, the relationship between ROCK signaling and p53 pathway was found. Further, mechanistic research attributed the regulatory function of CCNA2 on p53 pathway to the involvement of DNA damage. Conclusion Our study revealed the downregulation of CCNA2 in first-trimester chorionic villi of patients with RM and showed that this protein regulates migration, proliferation, and apoptosis in HTR8 cells, suggesting that CCNA2 may be the potential therapeutic target for RM.