Endometrial epithelial–mesenchymal transition (EMT) by menstruation-related inflammatory factors during hypoxia

Abstract

Endometriosis is characterised by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal hemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, hypoxia is a well-known inducer of fibrosis that may be associated with epithelial-mesenchymal transition (EMT). However, the complex molecular interactions between hypoxia and proinflammatory menstruation-related factors, PGE2 and thrombin, a PAR1 agonist, on EMT in endometriosis have not been fully characterised. To explore the effects of hypoxia and proinflammatory factors on EMT-like changes in endometrial cells, we determined the effects of PGE2 and thrombin (P/T) on EMT marker expression and cell migration in three dimensional cultured human endometrial epithelial (EECs) and stromal (ESCs) cells. Treatment of EECs with P/T under hypoxia stimulated cell migration, increased the expression of mesenchymal N-cadherin, vimentin and C-X-C chemokine receptor type 4 (CXCR4), and reduced the expression of epithelial E-cadherin. Furthermore, treatment with C-X-C motif chemokine ligand 12 (CXCL12), a ligand for CXCR4, increased EMT marker expression and cell migration. In ESCs, P/T or estrogen treatment under hypoxic conditions increased the expression and secretion of CXCL12. Taken together, our data show that hypoxic and proinflammatory stimuli induce EMT, cell migration and inflammation in EECs, which was increased by CXCL12 derived from ESCs. These data imply that inflammatory mediators in retrograde menstrual fluid contribute to ectopic endometrial EMT and migration in the presence of peritoneal hypoxia.

LncRNA BANCR Promotes Endometrial Stromal Cell Proliferation and Invasion in Endometriosis via the miR-15a-5p/TRIM59 Axis

“…EM is a gynecological disorder with malignant potential and remains a challenge in the clinic due to the lack of therapies with curable efficacy [ 7 ]. ECSs are identified as the major resident cells in the endometrium and alterations in their behaviors, such as proliferation, invasion, migration, and epithelial-mesenchymal transition, are associated with the pathogenesis of EM [ 33 , 36 , 37 ]. In addition, lncRNAs are involved in gene regulation in EM and the alteration of lncRNA expression level affects EM progression [ 38 ].…”

Toll-like receptor signaling pathway triggered by inhibition of serpin A1 stimulates production of inflammatory cytokines by endometrial stromal cells

“…The concentrations of IL-1β, IL-6, and IL-8 (encoded by the CXCL8 gene) in the medium were measured using an ELISA kit (Human IL-6 Simple Step ELISA Kit; Abcam, Tokyo, Japan). The concentration of IFN-β in the supernatant was also measured using an ELISA kit (Human IFN-beta Sandwich ELISA kit; Proteintech) ( 7 ).…”

“…In endometriosis-like lesions, levels of interleukin 6 (IL-6) and prostaglandin E2 (PGE2) increased, whereas that of SERPINA1 (known as alpha-1 antitrypsin) decreased (5,6). Treatment of endometrial stromal and glandular epithelial cells with PGE2 and thrombin significantly increases secretion of IL-6, as well as by endometriotic lesions (5,7,8).. Notably, the IL-6 and IL-8 concentrations in the serum of patients with endometriosis are higher than those in healthy women (9,10).…”

Menstruation Dysregulation and Endometriosis Development

“…These transcription factors could be potential treatment targets, and inhibitors of the Jun pathway like the c-Jun NH 2 -terminal kinase inhibitor significantly reduced the amount of active endometriotic lesions in baboon models (46). Other studies also found increased mesenchymal transition markers like N-cadherin and vimentin in endometrial epithelial cells under hypoxic and inflammatory conditions (47,48). Meanwhile, invasive activity and mesenchymal changes of Ishikawa cells decreased when HIF-1a levels were down-regulated (48).…”