Endometrial epithelial cells-derived exosomes deliver microRNA-30c to block the BCL9/Wnt/CD44 signaling and inhibit cell invasion and migration in ovarian endometriosis

Abstract

Endometriosis (EMs) is a benign gynecological disorder showing some tumor-like migratory and invasive phenotypes. This study intended to investigate the role of microRNA-30c (miR-30c) in EMs, which is involved with B-cell lymphoma 9 (BCL9), an activator of the Wnt/β-catenin signaling pathway. EMs specimens were clinically collected for determination of miR-30c and BCL9 expression. Exosomes were isolated from endometrial epithelial cells (EECs), and the uptake of exosomes by ectopic EECs (ecto-EECs) was characterized using fluorescence staining and confocal microscopy. The binding of miR-30c to BCL9 was validated by dual-luciferase reporter assay. Artificial modulation (up- and down-regulation) of the miR-30c/BCL9/Wnt/CD44 regulatory cascade was performed to evaluate its effect on ecto-EEC invasion and migration, as detected by Transwell and wound healing assays. A mouse model of EMs was further established for in vivo substantiation. Reduced miR-30c expression and elevated BCL9 expression was revealed in EMs ectopic tissues and ecto-EECs. Normal EECs-derived exosomes delivered miR-30c to ecto-EECs to suppress their invasive and migratory potentials. Then, miR-30c was observed to inhibit biological behaviors of ecto-EECs by targeting BCL9, and the miR-30c-induced inhibitory effect was reversed by BCL9 overexpression. Further, miR-30c diminished the invasion and migration of ecto-EECs by blocking the BCL9/Wnt/CD44 axis. Moreover, miR-30c-loaded exosomes attenuated the metastasis of ecto-EEC ectopic nodules. miR-30c delivered by EECs-derived exosomes repressed BCL9 expression to block the Wnt/β-catenin signaling pathway, thus attenuating the tumor-like behaviors of ecto-EECs in EMs.

Activation of CD44 signaling in leader cells induced by tumor-associated macrophages drives collective detachment in luminal breast carcinomas

“…As previously reported, PLAU and its receptor PLAUR were involved in regulating cell adhesion and promoting tumor cell migration [25,26], while c-Myc and AXL were associated with EMT, invasiveness, and migration [27,28]. Notably, CD44 was also upregulated in the disseminating leader cells and was reported to be associated with the functions of these genes (c-Myc, PLAU, PLAUR, and AXL) [29,30]. Moreover, from our previous study, CD44 switching was found to be related to the stemness and plasticity of cancer cells, showing the capability to give rise to collective invasion [8].…”

Macrophages and small extracellular vesicle mediated-intracellular communication in the peritoneal microenvironment: Impact on endometriosis development

“…Together, the evidence suggests endometriosis-specific stromal derived sEVs may contribute to disease progression. Recently, miR-30c encapsulated in sEVs derived from endometriotic epithelial cells was found to supress epithelial cell invasion and migration and attenuate endometriosis progression in a mouse model (94). These in vitro and in vivo studies indicate that the peritoneal microenvironment will likely contain a variety of sEVs, and that these sEVs may carry key factors instrumental in the pathogenesis of endometriosis.…”

“…Together, the evidence suggests endometriosis-specific stromal derived sEVs may contribute to disease progression. Recently, miR-30c encapsulated in sEVs derived from endometriotic epithelial cells was found to supress epithelial cell invasion and migration and attenuate endometriosis progression in a mouse model ( 94 ).…”

Endometriosis Stem Cells as a Possible Main Target for Carcinogenesis of Endometriosis-Associated Ovarian Cancer (EAOC)

“…The concentration of soluble CD44 in the serum and endometrial fluid of endometriosis patients was higher than that of healthy women [82]. In the mouse model of endometriosis, the role of epigenetic regulation of B-cell lymphoma 9 (BCL9)/Wnt/β-catenin/CD44 signaling pathway indicated, that exosomes containing miR-30c were able to inhibit invasion and migration of endometrial epithelial cells in ectopic lesions by blocking BCL9/Wnt/CD44 axis [83].…”