Osteopontin Promoting The Pathogenesis Of Endometriosis And Changes In Cell Invasion And Migration Through Activation Of Nf-Kappa B Signaling In Endometrial Epithelial Cells

Background: Endometriosis, characterized by the appearance of active endometrial tissue (glands and stroma) outside the uterine cavity, leads to dysmenorrhea, chronic pelvic pain, infertility and/or clinical symptoms that seriously affect the health of women. The etiology and pathogenesis of endometriosis are largely unknown. Oncology studies have shown that osteopontin (OPN) binds to its receptor to activate nuclear factor-kappa B p65 (NF-kappa B p65) which relies upon the MAPK/PI3K pathway, thus promoting the secretion of urokinase-type plasminogen activator and matrix metalloproteinases (MMPs) which mediate cell invasion and migration to induce tumor formation and metastasis. Since the characteristics of endometriosis, such as adhesion, invasion and metastasis, are similar to those in cancer, vascular endothelial growth factor, OPN, MMP-9, and NF-kappa B have been associated with the development of endometriosis. These factors may be closely associated with ectopic endometrial adhesion and invasiveness. However, the role of OPN in regulating the abnormal expression of endometrial epithelial cells (EECs) remains unknown. We tested the hypothesis that OPN plays an important role in regulating MMP-9 expression levels to change cell invasion and migration via NF-kappa B-mediated signaling pathways. Methods: We used immunohistochemistry to detect the expression of OPN and NF-kappa B p65 proteins and mRNA in eutopic and ectopic endometria of patients with endometriosis. Primary culture and identification of endometrial epithelial cells (EECs) was performed to investigate OPN and NF-kappa B p65 expression levels in EECs after OPN-specific small interfering RNA (siRNA) downregulation and plasmid upregulation. Transwell assays were carried out to investigate the invasiveness and migration ability of EECs. Results: Expression levels of OPN and NF-kappa B p65 proteins in eutopic and ectopic endometria of endometriosis patients were higher than in normal endometria. Treatment of EECs with siRNA directed against OPN reduced OPN, NF-kappa B nuclear translocation proteins and mRNA expression. Cell invasion and migration and NF-kappa B signaling was suppressed significantly by OPN siRNA. These effects of OPN and NF-kappa B p65 on EECs were also demonstrated in OPN-overexpressing cells. Conclusion: Our results suggest that OPN regulates NF-kappa B p65 and MMP-9 expression in EECs by activating NF-kappa B signaling, providing new insights into the mechanism of invasion and metastasis in endometriosis.