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, ß-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.
Clinical trial identification
Legal entity responsible for the study
China National Natural Scientific Fund (81502306),Tianjin Medical University Research Project (2014KYQ08)
All authors have declared no conflicts of interest.