21P - MiR-340 inhibits breast cancer cell progression by revering EZH2 mediated miRNAs dysregulated expression

Abstract

The anti-tumor activity of miR-340 has been recently characterized in breast tumor cells. However, the mechanisms underlying miR-340 induced cell growth and invasion in triple-negative breast cancer (TNBC) have not been well elucidated. In this study, we found that miR-340 expression was negative correlated with EZH2 expression in TNBC sample tissues and cell lines. Subsequent luciferase reporter assay confirmed that EZH2 (Enhancer of zeste homolog 2) was a novel molecule target of miR-340. Upregulated MiR-340 expression levels by mimics transfection significantly inhibited the MDA-MB-231 and MDA-MB-468 breast cancer cells proliferation, invasion and migration activity, and also induced more cell apoptosis. Meanwhile, miR-340 upregulation inhibited the tumor growth in an orthotopic MDA-MB-231 breast cancer mouse models. Furthermore, we found the reduced EZH2 expression by miR-340 mimics transfection also decreased the DNMT1, H3K27me3, &bgr;-catenin and P-STAT3 expressions, which ultimately resulted in the blockage of miR-21 activity and the induction of miR-200a/b expressions. our results identified miR-340 as a tumor suppressor in TNBC, moreover, an EZH2 medicated regulatory loop was also established. Post-transcriptional suppression of EZH2 expression not only blocked STAT3 mediated miR-21 trans-activation, but also reversed the miR200a/b silencing by reducing DNMT1 and H3K27me3 expression. MiR-21 inhibition and miR-200a/b expression trigged by miR-340 cooperated in the TNBC progression.