Abstract

Trophoblasts, integral to placental function, are pivotal in implantation and in establishing the maternal–fetal interface. Abnormal proliferation and invasion of trophoblasts can significantly contribute to the onset and progression of recurrent spontaneous miscarriage. Tumor necrosis factor ligand superfamily member 3B (TNFSF13B) is a classical B-cell activating factor that plays an important role in regulating the proliferation, growth, differentiation and invasion of a variety of cells, and is involved in the pathogenesis of multiple human diseases. However, its role in unexplained recurrent miscarriage (URM) remains unclear. In the present study, we found that TNFSF13B expression was significantly decreased in trophoblast cells of villous tissue from unexplained recurrent miscarriage(URM) patients. TNFSF13B promoted the proliferation and invasion of HTR-8 cells. Using dual luciferase reporter and chromatin immunoprecipitation assays, we identified GATA-binding protein 3 (GATA3) as a key transcription factor that binds to the core promoter region of TNFSF13B and regulates TNFSF13B expression. Overexpression of F-box and WD-repeat domain-containing protein 7 (FBXW7) ubiquitin-degraded GATA3, resulting in decreased TNFSF13B expression. TNFSF13B regulates the proliferation and invasion of trophoblast cells through PI3K/Akt signaling pathway, which is inhibited and eventually leads to abortion. Taken together, our findings suggest that TNFSF13B, GATA3 and FBXW7 may be involved in the pathogenesis of URM and may serve as potential therapeutic targets.