\u0394Np63\u03b1-induced DUSP4/GSK3\u03b2/SNAI1 pathway in epithelial cells drives endometrial fibrosis

Guangfeng Zhao,Limin Wang,Dan Liu,Hui Zhu,Jianwu Dai,Yun Cao,Haining Lv,Huiyan Wang,Simin Yao,Yan Zhou,Zhenhua Zhou,Peipei Jiang,Chenyan Dai,Yali Hu,Minmin Song,Ruotian Li,Qianwen Wu

doi:10.1038/s41419-020-2666-y

Abstract

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 ΔNp63α is associated with fibrosis process and epithelial dysfunction in endometria of patients with intrauterine adhesions (IUAs). Since ΔNp63α 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 ΔNp63α in EECs. In transcriptomic analysis, we found that diverse signaling pathways regulated by ΔNp63α were involved in pro-EMT. We demonstrated that the DUSP4/GSK-3β/SNAI1 pathway was critical in transducing the pro-EMT signals initiated by ΔNp63α, while bFGF reversed ΔNp63α-induced EMT and endometrial fibrosis both in vitro and in vivo by blocking DUSP4/GSK3β/SNAI1 pathway. Taken together, our findings are important to understand the molecular mechanisms of endometrial fibrosis and to provide potential therapeutic targets.

Highlights

Epithelial homeostasis is essential for tissue function[1,2].Loss of the epithelial homeostasis leads to tissue remodeling and dysfunction[3]
The results showed that the SNAI1 protein was upregulated to 11.3fold of the control level, E-cadherin was decreased by 52.8%, and N-cadherin and α-SMA were increased by a 1.85-fold and 3.07-fold, respectively (Supplementary Fig. 5A), which is in agreement with epithelial cells (EECs)–epithelial-to-mesenchymal transition (EMT)
intrauterine adhesions (IUAs) is characterized with endometrial fibrosis, yet the pathological process is mostly unknown

Summary

Introduction

Epithelial homeostasis is essential for tissue function[1,2]. Loss of the epithelial homeostasis leads to tissue remodeling and dysfunction[3]. In spite of cyclical endometrial shedding and rehealing in every menstrual cycle, the epithelial homeostasis in endometrium is well-developed and maintained. The mechanism to maintain the relatively stable epithelial phenotype in endometrial epithelial cells (EECs) remains largely unknown[4]. Since epithelium is directly exposed to exogenous injuries, such as intrauterine procedures, it is likely that these injuries disrupt the epithelial homeostasis and result in local tissue. ΔNp63α is the main form of p63 in epithelial cells[9]. It is known that during uterine development, p63 is expressed in the epithelial cells of the paramesonephric ducts but is no longer expressed in EECs after the fusion of bilateral paramesonephric ducts[10]. The expansion of the p63 lineage in pathological conditions is associated with

Methods

Results

Conclusion