Epiregulin promotes trophoblast epithelial-mesenchymal transition through poFUT1 and O-fucosylation by poFUT1 on uPA
Epiregulin promotes trophoblast epithelial-mesenchymal transition through poFUT1 and O-fucosylation by poFUT1 on uPA
复制标题
上皮调节蛋白通过 poFUT1 和 uPA 上 poFUT1 的 O-岩藻糖基化促进滋养层上皮间质转化
DOI：
10.1111/cpr.12745
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发表时间：
2019-12-30
影响因子：
8.5
通讯作者：
Yan, Qiu
中科院分区：
文献类型：
--
作者：
Cui, Xinyuan;Wang, Hao;Yan, Qiu
目的细胞滋养细胞向间充质样间质外滋养细胞的转化是胚胎成功着床的必要条件，转化不充分可能导致流产。表调节蛋白是一种新的生长因子，在生殖过程中起着重要的作用。许多蛋白质的糖基化在繁殖过程中是至关重要的。蛋白O-聚焦转移酶1 （Protein O- focusyltransferase 1, poFUT1）是生物合成特定糖蛋白上O-聚焦的关键酶。尿激酶型纤溶酶原激活物（uPA）在Thr上含有O-聚焦结构域（18）。然而，表调节蛋白和poFUT1在滋养细胞上皮-间质转化（EMT）过程中的功能、表调节蛋白对poFUT1的调控机制以及由此产生的O-聚焦uPA仍不清楚。材料与方法采用酶联免疫吸附法（ELISA）和免疫印迹法（Western blot）检测非妊娠、妊娠和流产患者血清表调节蛋白（epepregulin）和poFUT1水平。利用两种滋养细胞系和小鼠妊娠模型，我们研究了表调节蛋白和poFUT1在滋养细胞EMT过程中的潜在机制。结果妊娠妇女血清表调节素和poFUT1水平高于未妊娠妇女，流产妇女血清表调节素和poFUT1水平明显低于妊娠妇女。结果表明，表调节蛋白上调poFUT1的表达，增加uPA上的O-聚焦，进一步激活PI3K/Akt信号通路，促进滋养细胞的EMT行为和胚胎着床。结论流产患者表调节素和poFUT1水平低于早期妊娠妇女。表调节蛋白通过poFUT1催化uPA的O-聚焦促进滋养细胞EMT。表调节蛋白和poFUT1可能被认为是流产的潜在诊断生物标志物和有用的治疗靶点。
Objectives The transformation of cytotrophoblasts into mesenchymal-like extravillous trophoblasts is necessary for successful embryo implantation, and the inadequate transformation may cause abortion. Epiregulin, which is a new growth factor, plays important roles in the reproductive processes. The glycosylation of many proteins in reproduction processes is critical. Protein O-fucosyltransferase 1 (poFUT1) is the key enzyme for the biosynthesis of O-fucosylation on the specific glycoproteins. Urokinase-type plasminogen activator (uPA) contains O-fucosylated domain on Thr(18). However, the functions of epiregulin and poFUT1 in the trophoblast epithelial-mesenchymal transition (EMT) process, the regulatory mechanism of epiregulin on poFUT1 and the resulting O-fucosylated uPA remain unclear. Materials and methods We employed ELISA and Western blot to detect serum levels of epiregulin and poFUT1 from non-pregnancy women, pregnancy women and abortion patients. Using two trophoblast cell lines and a mouse pregnancy model, we investigated the underlying mechanisms of epiregulin and poFUT1 in trophoblast EMT process. Results Serum levels of epiregulin and poFUT1 were higher in pregnant women compared with non-pregnant women, and their levels were significantly decreased in abortion patients compared with pregnant women. The results showed that epiregulin upregulated poFUT1 expression and increased O-fucosylation on uPA, which further activated the PI3K/Akt signalling pathway, facilitating EMT behaviour of trophoblast cells and embryo implantation in the mouse pregnant model. Conclusions Level of epiregulin and poFUT1 is lower in abortion patients than early pregnancy women. Epiregulin promotes trophoblast EMT through O-fucosylation on uPA catalysed by poFUT1. Epiregulin and poFUT1 may be suggested as the potential diagnostic biomarkers and useful treatment targets for abortion.