Endometriosis-derived exosomal MicroRNA-125b-5p downregulates phosphatidylinositol 3-Kinase/Protein Kinase B signaling pathways via vascular endothelial growth factor to decelerate endometriosis progression.

BACKGROUND

Endometriosis (EMs) is a chronic enigmatic gynecological disorder which pathogenesis have not been fully elucidated. Exosomes have been proven to participate in endometriosis. However, the role of exosomes in the pathogenesis of EMs remains poorly defined.

METHODS

Exosomes were isolated from cyst fluid of EMs patients and pelvic fluid of non-EMs patients, and characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot. Exosomal miRNAs were performed by small RNA sequencing. Q-PCR and cell function were performed to identify the relationship between exosomal miRNAs and endometriosis. Dual luciferase reporter assay, cell transfection, Q-PCR, Western blotting and CCK8 assays, Transwell assays and Boyden assays were conducted to explore the regulatory effects of exosomal miRNA on EMs pathogenesis in vitro using primary human endometrial stromal cells (HESCs) derived from endometriotic lesions.

RESULTS

Compare with non-EMs group, there are 118 miRNAs were up-regulated and 40 miRNAs were down-regulated in CF group, meanwhile 22 miRNAs were up-regulated and 32 miRNAs were down-regulated in PF group. Q-PCR verified that miR-125b-5p, miR-328-3p, miR-125a-5p, miR-30e-3p were significant down-regulated, whereas miR-3141, miR-223-3p, miR-142-5p, miR-1246 were significant up-regulated in EMs patients. ROC analysis indicated that miR-125b-5p (AUC = 0.925, p < 0.001) was highly correlated with EMs pathogenesis. Dual luciferase reporter assay results demonstrated miR-125b-5p directly targeted VEGF gene. MiR-125b-5p suppressed endometrial stromal cells proliferation, migration and invasion by regulating the Phosphatidylinositol 3-Kinase (PI3K) /Protein Kinase B (AKT) signaling pathway.

CONCLUSION

Exosomal miR-125b-5p was highly correlated with EMs, and it regulates the PI3K/Akt signaling pathways through VEGF to inhibit endometrial stromal cells proliferation, migration and invasion, acting as an important suppressing miRNA in endometriosis pathogenesis.