3,6-dihydroxyflavone suppresses the epithelial-mesenchymal transition, migration and invasion in endometrial stromal cells by inhibiting the Notch signaling pathway

摘要

OBJECTIVE: Endometriosis is a common disease in women of reproductive age. Characteristics of endometriosis include invasion, metastasis, and recurrence, which are similar to those of malignant tumors. However, the etiology and pathogenesis of endometriosis are still not clear. This study aims to explore the mechanism of 3,6-dihydroxyflavone (3,6-DHF) in the development of endometriosis. PATIENTS AND METHODS: Primary cultured ovarian ectopic endometrial stromal cells (OvESCs) were utilized as the in vitro model of endometriosis. OvESCs were treated with different concentrations of 3,6-DHF. The expressions of proteins related to epithelial-mesenchymal transition (EMT) and Notch signal pathway were detected by Western blot. The mRNA expressions of related genes were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The viability of treated cells was detected by transwell assay. The impact of 3,6-DHF on ectopic lesions was explored after the animal model of endometriosis was successfully established. RESULTS: With the increased concentration of 3,6-DHF in OvESCs, the protein and mRNA expressions of E-cadherin were gradually increased, while the protein and mRNA expressions of N-cadherin, Twist, Snail, and Slug were decreased. 3,6-DHF treatment inhibited the migration and invasion ability of OvESCs in a dose-dependent manner. In the endometriosis model of severe combined immunodeficient (SCID) mice, lesions in the 3,6-DHF treated group were significantly smaller than those of the control group. The same changes were found in the endometriosis model of Sprague Dawley (SD) rats. Protein expressions of Notch1, NICD, and Hes-1 in OvESCs were inhibited by 3,6-DHF in a dose-dependent manner. 3,6-DHF can inhibit the binding of NICD-CSL-MAML complex in OvESCs, thereby inhibiting the expressions of proteins related to Notch signaling pathway in vitro. CONCLUSIONS: 3,6-DHF can inhibit the development of EMT, migration, and invasion of endometrial stromal cells by inhibiting the Notch signaling pathway.