SPRY4 regulates trophoblast proliferation and apoptosis via regulating IFN-γ-induced STAT1 expression and activation in recurrent miscarriage
SPRY4 regulates trophoblast proliferation and apoptosis via regulating IFN-γ-induced STAT1 expression and activation in recurrent miscarriage
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DOI：
10.1111/aji.13234
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发表时间：
2020-04-06
影响因子：
3.6
通讯作者：
Lin, Yi
中科院分区：
文献类型：
--
作者：
Qin, Shi;Zhang, Yan;Lin, Yi
问题滋养层功能失调是复发性流产（RM）的主要原因之一，这使1%-5%的育龄夫妇感到沮丧。Sprouty 4（SPRY 4）被认为是一种肿瘤抑制因子，对细胞活力起负面作用。然而，它在调节滋养层细胞的行为在母胎界面的作用仍然在很大程度上unknowed.Method的研究收集早期妊娠绒毛样品RM患者和健康对照（HC），以确定SPRY 4在人类胎盘在妊娠早期的表达。通过体外特异性短干扰RNA（siRNA）对SPRY 4或SPRY 4过表达慢病毒进行干扰，建立了HTR 8/SVneo细胞系，以阐明滋养层细胞的功能。此外，基因表达谱芯片分析进行了探索下游分子和pathways.Results我们的研究结果显示，SPRY 4的表达显着增加，在早期妊娠RM患者的细胞滋养层细胞相比，HC。此外，SPRY 4过表达抑制滋养层细胞增殖，并在体外加速凋亡，而SPRY 4敲低逆转这些作用。IFN-γ通过PI 3 K/AKT途径促进SPRY 4的表达和STAT 1的磷酸化。结论SPRY 4可能通过上调IFN-γ/PI 3 K/AKT诱导的STAT 1活化而负调节滋养细胞功能。高水平的SPRY 4和STAT 1可能有助于RM的发生和进展，阻断这两个靶点可能是RM患者的一种新的治疗策略。
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-gamma -induced STAT1 expression and activation were involved in the regulation of trophoblast proliferation and apoptosis by SPRY4, and IFN-gamma 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-gamma/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.