ΔNp63α-induced DUSP4/GSK3β/SNAI1 pathway in epithelial cells drives endometrial fibrosis

• Published in: Cell death & disease Vol. 11; no. 6; p. 449
• Main Authors: Zhao, Guangfeng, Li, Ruotian, Cao, Yun, Song, Minmin, Jiang, Peipei, Wu, Qianwen, Zhou, Zhenhua, Zhu, Hui, Wang, Huiyan, Dai, Chenyan, Liu, Dan, Yao, Simin, Lv, Haining, Wang, Limin, Dai, Jianwu, Zhou, Yan, Hu, Yali
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.06.2020; Springer Nature B.V
• Subjects: 13/51; 13/95; 38/91; 631/337; 64; 64/60; 692/699/2732; 82; 96; 96/95; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Ectopic expression; Endometrium; Endometrium - metabolism; Epithelial cells; Epithelial Cells - metabolism; Female; Fibroblast growth factor 2; Fibrosis; Fibrosis - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Homeostasis; Humans; Immunology; Life Sciences; Mesenchyme; Mice; Molecular modelling; Phenotypes; Signal Transduction; Snail protein; Therapeutic applications
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2666-y

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.