Abstract
BackgroundMelatonin is a potential therapeutic agent for endometriosis, but its molecular mechanism is unclear. Here, we investigated the effect of melatonin on the epithelial-mesenchymal transition (EMT) in endometriotic endometrial epithelial cells and explored the pathway that might be involved.MethodsThis hospital-based study included 60 women of reproductive age using the endometrium for immunohistochemistry, 6 women of reproductive age undergoing bilateral tubal ligation and 6 patients with endometriosis for isolation of endometrial epithelial cells or subsequent analysis, respectively. We examined the expression of Notch1/Numb signaling and EMT markers by immunohistochemistry analysis and western blot analysis, the invasion and migration of endometrial epithelial cells by transwell assays, and the cell proliferation by CCK8 assays.ResultsCompared with normal endometrium, the endometriotic eutopic endometrium showed increased expression of Notch1, Slug, Snail, and N-cadherin, and decreased expression of E-cadherin and Numb. Melatonin or Notch inhibition by specific inhibitor blocked 17β-estradiol-induced cell proliferation, invasion, migration and EMT-related markers in both normal and endometriotic epithelial cells.ConclusionsOur data suggest that aberrant expression of Notch1/Numb signaling and the EMT is present in endometriotic endometrium. Melatonin may block 17β-estradiol-induced migration, invasion and EMT in normal and endometriotic epithelial cells by upregulating Numb expression and decreasing the activity of the Notch signaling pathway.
Highlights
Melatonin is a potential therapeutic agent for endometriosis, but its molecular mechanism is unclear
Aberrant expression of notch/numb signaling and epithelial-mesenchymal transition (EMT) markers in endometriotic endometrium The expression of Notch/Numb signaling and EMT markers in normal endometria and in endometriotic eutopic endometria were determined by immunohistochemical analysis
We found that aberrant expression of EMT-related markers existed in endometriotic eutopic endometrium, and estrogen promoted the migration, invasion and EMT phenotype in normal and endometritic eutopic epithelial cells, while melatonin and the blocking of Notch signaling inhibited 17β-estradiol-induced migration, invasion and epithelial-mesenchymal transition in normal and endometriotic endometrial epithelial cells
Summary
Melatonin is a potential therapeutic agent for endometriosis, but its molecular mechanism is unclear. We investigated the effect of melatonin on the epithelial-mesenchymal transition (EMT) in endometriotic endometrial epithelial cells and explored the pathway that might be involved. Epithelial-mesenchymal transition (EMT), which is characterized by an increased rate of cellular migration, invasion properties and increased resistance to apoptosis, is considered essential for the formation and progression of endometriosis [3,4,5]. Key transcription factors including Snail, Slug and Twist drive the EMT process, which along with cleaved and degraded E-cadherin and increased expression of mesenchymal-related. We found that the expression of both Notch, a key signaling factor involved in EMT regulation, and EMT-related proteins was upregulated in the ectopic endometrium of adenomyosis compared with those in normal endometrium [8]
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