Estrogen attenuates TGF-β1-induced EMT in intrauterine adhesion by activating Wnt/β-catenin signaling pathway

Abstract

Although estrogen has crucial functions for endometrium growth, the specific dose and underlying molecular mechanism in intrauterine adhesion (IUA) remain unclear. In this study, we aimed to investigate the effects of estrogen on epithelial-mesenchymal transition (EMT) in normal and fibrotic endometrium, and the role of estrogen and Wnt/β-catenin signaling in the formation of endometrial fibrosis. CCK-8 and immunofluorescence assay were performed to access the proliferation of different concentrations of estrogen on normal human endometrial epithelial cells (hEECs). qRT-PCR and western blot assay were utilized to explore the effect of estrogen on EMT in normal and fibrotic endometrium, and main components of Wnt/β-catenin signaling pathway in vitro . Hematoxylin and eosin and Masson staining were used to evaluate the effect of estrogen on endometrial morphology and fibrosis in vivo . Our results indicated that the proliferation of normal hEECs was inhibited by estrogen at a concentration of 30 nM accompanied by upregulation of mesenchymal markers and downregulation of epithelial markers. Interestingly, in the model of transforming growth factor β1 (TGF-β1)-induced endometrial fibrosis, the same concentration of estrogen inhibited the process of EMT, which might be partially mediated by regulation of the Wnt/β-catenin pathway. In addition, relatively high doses of estrogen efficiently increased the number of endometrial glands and reduced the area of fibrosis as determined by the reduction of EMT in IUA animal models. Taken together, our results demonstrated that an appropriate concentration of estrogen may prevent the occurrence and development of IUA by inhibiting the TGF-β1-induced EMT and activating the Wnt/β-catenin pathway.

G protein‐coupled estrogen receptor 1 inhibits the epithelial–mesenchymal transition of goat mammary epithelial cells via NF‐κB signalling pathway

“…It is known that oestrogen participates in regulating EMT process. Oestrogen efficiently suppressed the EMT, contributing to reducing the area of fibrosis (Cao et al 2020). In GMECs, the inhibitory effect on EMT by oestrogen was revealed (Figure 2).…”

“…In addition, oestrogen (E2) is found to participate in the regulation of EMT progression. Oestrogen efficiently increased the number of endometrial glands and reduced the area of fibrosis as determined by the reduction in EMT in intrauterine adhesion animal models (Cao et al 2020). G protein-coupled estrogen receptor 1 (GPER1), a membrane estrogen receptor, is discovered to involve in the regulation of cell proliferation, migration and invasion (Molina et al 2017;Prossnitz & Barton, 2011).…”

MiR-543 Inhibits the Migration and Epithelial-To-Mesenchymal Transition of TGF-β-Treated Endometrial Stromal Cells via the MAPK and Wnt/β-Catenin Signaling Pathways

“…Furthermore, numerous studies have indicated that transforming growth factor (TGF)-β is a cytokine that participates in regulating diverse biological functions, including cell proliferation, apoptosis, and differentiation [ 11 , 12 ]. Importantly, previous studies have reported that TGF-β can induce endometrial fibrosis [ 13 , 14 ] and TGF-β treated ESC can serve as the in vitro model of IUA [ 15 , 16 ].…”

Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision

“…Therefore, subsequent IUA management is considered necessary when IUA occurs. Thus far, there have been many publications addressing the topic of the management of IUA [ 23 , 24 , 26 , 27 , 28 , 29 , 30 , 35 , 40 , 43 , 57 , 58 , 59 , 62 , 64 , 131 , 132 , 133 , 134 , 135 , 136 , 138 , 139 , 140 , 141 , 142 , 155 , 164 , 165 , 166 , 167 , 168 ].…”