ΔNp63α-induced DUSP4/GSK3β/SNAI1 pathway in epithelial cells drives endometrial fibrosis
ΔNp63α-induced DUSP4/GSK3β/SNAI1 pathway in epithelial cells drives endometrial fibrosis
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上皮细胞中αNp63α诱导的 DUSP4/GSK3 beta/SNAI1 通路驱动子宫内膜纤维化
DOI：
10.1038/s41419-020-2666-y
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发表时间：
2020-06-11
影响因子：
9
通讯作者：
Hu, Yali
中科院分区：
文献类型：
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作者：
Zhao, Guangfeng;Li, Ruotian;Hu, Yali
上皮稳态在维持子宫内膜功能中起着至关重要的作用。但上皮细胞在子宫内膜纤维化中的作用研究较少。之前，我们发现Delta Np63 α的异位表达与子宫内粘连（IUAs）患者子宫内膜的纤维化过程和上皮功能障碍有关。由于Delta Np63 α深度参与维持上皮稳态，因此我们在此重点研究其在子宫内膜纤维化背景下调节子宫内膜上皮细胞（EECs）功能和表型的作用。我们在IUA患者的EECs中发现了典型的2型上皮到间质转化（EMT），这一过程是由EECs中δ Np63 α的强制表达诱导的。在转录组学分析中，我们发现Delta Np63 α调控的多种信号通路参与了前emt。我们证明DUSP4/GSK-3 β /SNAI1通路在Delta Np63 α启动的前EMT信号转导中起关键作用，而bFGF通过阻断DUSP4/GSK3 β /SNAI1通路，在体外和体内逆转Delta Np63 α诱导的EMT和子宫内膜纤维化。综上所述，我们的发现对于理解子宫内膜纤维化的分子机制和提供潜在的治疗靶点具有重要意义。
Epithelial homeostasis plays an essential role in maintaining endometrial function. But the epithelial role in endometrial fibrosis has been less studied. Previously, we showed that ectopic expression of Delta Np63 alpha is associated with fibrosis process and epithelial dysfunction in endometria of patients with intrauterine adhesions (IUAs). Since Delta Np63 alpha is profoundly involved in maintaining the epithelial homeostasis, we hereby focused on its roles in regulating the function and phenotype of endometrial epithelial cells (EECs) in context of endometrial fibrosis. We identified a typical type 2 epithelial-to-mesenchymal transition (EMT) in EECs from IUA patients and this process was induced by the forced expression of Delta Np63 alpha in EECs. In transcriptomic analysis, we found that diverse signaling pathways regulated by Delta Np63 alpha were involved in pro-EMT. We demonstrated that the DUSP4/GSK-3 beta /SNAI1 pathway was critical in transducing the pro-EMT signals initiated by Delta Np63 alpha, while bFGF reversed Delta Np63 alpha -induced EMT and endometrial fibrosis both in vitro and in vivo by blocking DUSP4/GSK3 beta /SNAI1 pathway. Taken together, our findings are important to understand the molecular mechanisms of endometrial fibrosis and to provide potential therapeutic targets.