CircPTPN12/miR-21-5 p/∆Np63α pathway contributes to human endometrial fibrosis.

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

doi:10.7554/elife.65735

Abstract

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5 p to inhibit miR-21-5 p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT and administration of miR-21-5 p could reverse this process and improve endometrial fibrosis. Our findings revealed that the dysfunction of circPTPN12/miR-21-5 p/∆Np63α pathway contributed to the pathogenesis of endometrial fibrosis.

Highlights

Endometrial fibrosis is clinically characterized with intrauterine adhesions (IUA) and is often secondary to severe injury of endometrium including various uterine operations mainly repeated curettage
Since we found that the ectopic expression of DNp63a in epithelial cells (EECs) induces EEC–epithelial mesenchymal transition (EMT) and promotes endometrial fibrosis (Zhao et al, 2020), and DNp63a is regulated by multiple miRNAs (Candi et al, 2015; Lena et al, 2008; Rodriguez Calleja et al, 2016), we speculated whether circRNAs is involved in the pathogenesis of endometrial fibrosis by interacting with miRNAs
The histopathological results of the samples used for high-throughput sequencing showed endometrial fibrosis in IUA patients (Figure 1—figure supplement 1A)

Summary

Introduction

Endometrial fibrosis is clinically characterized with intrauterine adhesions (IUA) and is often secondary to severe injury of endometrium including various uterine operations mainly repeated curettage. Endometrial fibrosis is the most common reason of uterine infertility (Yu et al, 2008; March, 2011a; March, 2011b). Our study showed that the ectopic expression of DNp63a, a transcription factor, in the endometria of IUA patients triggers the epithelial mesenchymal transition (EMT) of endometrial epithelial cells (EECs) (EEC–EMT) to promote endometrial fibrosis (Zhao et al, 2020). Studies showed that let-7d is downregulated in EMT of the lung epithelial cells and downregulation of let-7d in mice causes lung fibrosis (Pandit et al, 2010). Studies showed that let-7d is downregulated in EMT of the lung epithelial cells and downregulation of let-7d in mice causes lung fibrosis (Pandit et al, 2010). miR-29b suppresses EMT of lung epithelial

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