SPRY4 regulates trophoblast proliferation and apoptosis via regulating IFN-γ-induced STAT1 expression and activation in recurrent miscarriage.,American Journal of Reproductive Immunology

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SPRY4 regulates trophoblast proliferation and apoptosis via regulating IFN-γ-induced STAT1 expression and activation in recurrent miscarriage.
American Journal of Reproductive Immunology ( IF 2.5 ) Pub Date : 2020-04-06 , DOI: 10.1111/aji.13234
Shi Qin ₁ , Yan Zhang ₂ , Jing Zhang ₃ , Fuju Tian ₁ , Liqun Sun ₁ , Xiaoying He ₁ , Xiaoling Ma ₁ , Jun Zhang ₂ , Xiao-Rui Liu ₁ , Weihong Zeng ₁ , Yi Lin ₁

Affiliation

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 maternal-fetal 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.

中文翻译：

SPRY4通过调节IFN-γ诱导的STAT1表达和反复流产中的激活来调节滋养细胞增殖和凋亡。

问题滋养层功能失调是反复流产（RM）的主要原因之一，它使育龄夫妇中1％-5％的人感到沮丧。Sprouty 4（SPRY4）被认为是一种肿瘤抑制因子，对细胞活力起着负面作用。然而，其在调节母婴界面滋养细胞行为中的作用仍然未知。研究方法从RM患者和健康对照组（HCs）收集早孕绒毛样品，以确定早孕期间人胎盘中SPRY4的表达。引入HTR8 / SVneo细胞系以体外转染针对SPRY4或SPRY4过表达的慢病毒的特异性短干扰RNA来阐明滋养细胞的功能。此外，进行了基因表达微阵列分析，以探索下游分子和途径。结果我们的结果显示，与HCs相比，RM患者孕早期的滋养细胞中SPRY4表达显着增加。此外，SPRY4的过表达在体外抑制滋养细胞增殖并加速细胞凋亡，而SPRY4的抑制则逆转了这些作用。从机制上讲，IFN-γ诱导的STAT1表达和激活参与SPRY4对滋养细胞增殖和凋亡的调控，而IFN-γ通过PI3K / AKT途径促进SPRY4表达和STAT1磷酸化。此外，RM患者的滋养细胞中STAT1和磷酸化STAT（p-STAT）的水平也上调，并且与SPRY4的表达呈正相关。结论我们的发现表明SPRY4可能通过上调IFN-γ/ PI3K / AKT诱导的STAT1激活而成为滋养细胞功能的负调节剂。高水平的SPRY4和STAT1可能有助于RM的发展和进程，而阻断任一靶点可能是RM患者的一种新颖治疗策略。

更新日期：2020-03-20

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