Oxytocin promotes invasiveness in endometriotic cells via miR-34a and miR-145: Influence of matrix metalloprotease-2

Abstract

Background: Endometriosis, a benign gynecological disease causing pain and infertility, rarely culminates into ovarian cancer. While its cause remains unclear, hormonal dysregulation plays a key role. Oxytocin is upregulated in the disease besides altered matrix metalloproteinases (MMPs) and microRNAs (miRs) that contribute to cellular invasion. Altered levels of miR-34a/miR-145 are reported in endometriosis and a link between oxytocin and miRNAs has also been observed in human myometrium. Hypothesis: Increased oxytocin might be responsible for cellular invasiveness due to reduced levels of miR-34a and miR-145 which is linked to high levels of MMP-2 activity in endometriotic cell lines. Materials and Methods: We used zymography and immunoblotting to assess MMP-2 expression and activity respectively in SK-OV-3 cells treated with mimics or inhibitors of miR-34a/miR-145 in the presence or absence of oxytocin. Invasion, migration, and EMT markers were also evaluated under similar treatments as well as oxytocin alone in SK-OV-3 and End1/E6E7 cells. Results: MMP-2 activity and expression slightly decreased with miR-34a and miR-145 treatment without oxytocin but increased with the addition of oxytocin. Oxytocin dose-dependently enhanced invasion and migration, while miRNA mimics reduced both, which were significantly induced by the addition of oxytocin. Oxytocin also increased n-cadherin and vimentin while reducing e-cadherin in the miRNA mimic group. Conclusion: Our study demonstrates that oxytocin induces cellular invasion and migration via downregulating miR-34a and miR-145 during endometriosis progression.