SPRY4 regulates trophoblast proliferation and apoptosis via regulating IFN‐γ‐induced STAT1 expression and activation in recurrent miscarriage

Abstract

Problem:The dysregulation of trophoblast functions is one of the leading causes of recurrent miscarriage (RM), which frustrates 1%-5% of couples of childbearing ages. Sprouty 4 (SPRY4) is considered as a tumour suppressor and exerts a negative role in cell viability. However, its role in regulating trophoblast behaviors at the maternalfetal interface remains largely unknown. Method of Study:First-trimester villous samples were collected from RM patients and healthy controls (HCs) to determine the SPRY4 expression in human placenta during early pregnancy. The HTR8/SVneo cell line was introduced to clarify trophoblast cell functions via transfecting with specific short interfering RNA against SPRY4 or SPRY4-overexpressing lentivirus in vitro. In addition, gene expression microarray analysis was performed to explore the downstream molecules and pathways. Results:Our results revealed that SPRY4 expression was significantly increased in the first-trimester cytotrophoblasts of RM patients compared with HCs. Furthermore, SPRY4 overexpression inhibited trophoblast proliferation and accelerated apoptosis in vitro, while SPRY4 knockdown reversed these effects. Mechanistically, IFN-γ -induced STAT1 expression and activation were involved in the regulation of trophoblast proliferation and apoptosis by SPRY4, and IFN-γ promoted SPRY4 expression and STAT1 phosphorylation through PI3K/AKT pathway. Additionally, both STAT1 and phosphorylated STAT (p-STAT) levels were also upregulated in trophoblasts from RM patients and positively correlated with SPRY4 expression. Conclusion:Our findings indicate that SPRY4 may act as a negative regulator of trophoblast functions through upregulating IFN-γ/PI3K/AKT-induced STAT1 activation. High levels of SPRY4 and STAT1 may contribute to RM development and progression, and blocking of either target could be a novel therapeutic strategy for RM patients. K E Y W O R D SIFN-γ, recurrent miscarriage, SPRY4, STAT1, trophoblast

First-Trimester Serum Cytokine Profile in Pregnancies Conceived After Assisted Reproductive Technology (ART) With Subsequent Pregnancy-Induced Hypertension

“…The establishment and maintenance of pregnancy poses great challenges to the maternal immune system. Uncoordinated maternal immunization, especially in the first trimester of pregnancy, will be a potential cause of a series of pregnancy complications (47,48). Currently, immunotherapy has been applied to the treatment of a variety of reproductive diseases, such as recurrent spontaneous abortion (RSA) and recurrent implantation failure (RIF) (49), while the immunotherapy against PIH still needs a long way to go.…”

Increased expression of IFN‑γ in preeclampsia impairs human trophoblast invasion via a SOCS1/JAK/STAT1 feedback loop

“…Following phosphorylation, STAT1 forms a homodimer and translocates to the nucleus where it binds to the conserved DNA sequence in the promoter region of the downstream target gene and activates its transcription (9). Previous studies have shown that IFN-γ could activate the JAK/STAT pathway in HTR-8/SVneo cells (41,42). STAT1 is phosphorylated at Ser727 and Tyr701 residues (43).…”

Expression of Alpha-Enolase 1 (ENO1) in Villi from Patients with Recurrent Miscarriage and Its Effect on Proliferation and Invasion of Villous Trophoblasts

“…Overexpression of ENO1 is also related to the progression of gliomas, and inhibiting ENO1 expression can inhibit the process of cell growth, migration and invasion by inactivating the PI3K/Akt pathway in glioma cells [16]. In previous studies on RM, cell proliferation, invasion, migration, and angiogenesis-related signaling pathways, such as the Wnt/β-catenin signaling pathway [17], the PI13K signaling pathway [18], and the ERK and other signaling pathways [19], participated in the occurrence and development of RM. Further research is needed to verify whether ENO1 affects the function of trophoblast cells through the above pathways.…”