J Cancer 2017; 8(15):3037-3048. doi:10.7150/jca.19315
MiR-340 Inhibits Triple-Negative Breast Cancer Progression by Reversing EZH2 Mediated miRNAs Dysregulated Expressions
1. 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research center, Tianjin Medical University Cancer Institute and Hospital;
2. Key laboratory of breast cancer prevention and therapy of ministry of education;
3. Key laboratory of cancer prevention and therapy, Tianjin, PR China;
4. School of Laboratory Medicine, Tianjin Medical University, Tianjin, PR China.
* These authors contributed equally to this work.
Shi Z, Li Y, Qian X, Hu Y, Liu J, Zhang S, Zhang J. MiR-340 Inhibits Triple-Negative Breast Cancer Progression by Reversing EZH2 Mediated miRNAs Dysregulated Expressions. J Cancer 2017; 8(15):3037-3048. doi:10.7150/jca.19315. Available from http://www.jcancer.org/v08p3037.htm
The anti-tumor efficacy of miR-340 has been recently characterized in cancers. However, the underlying mechanisms of miR-340 inhibited 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 negatively correlated with EZH2 (Enhancer of zeste homolog 2) expression in TNBC tissues and cell lines. Subsequent luciferase reporter assay confirmed that EZH2 was a novel molecule target of miR-340. Upregulated miR-340 levels by mimics transfection significantly inhibited the MDA-MB-231 and MDA-MB-468 breast cancer cells proliferation, invasion and migration, and induced more cell apoptosis. Meanwhile, miR-340 inhibited the tumor growth in an orthotopic MDA-MB-231 breast cancer mouse model. Furthermore, we found the reduced EZH2 expression by miR-340 mimics transfection decreased the DNMT1, H3K27me3, β-catenin and P-STAT3 expressions, which ultimately resulted in miR-21 activity blockage and miR-200a/b expression upregulation. The results of rescue experiments further confirmed that miR-340 inhibited triple-negative breast cancer progression through targeting EZH2. Taken together, our results identified miR-340 as a tumor suppressor in TNBC, moreover, an EZH2 medicated regulatory loop was established. Post-transcriptional suppression of EZH2 expression not only blocked STAT3 mediated miR-21 trans-activation, but also reversed the miR-200a/b silencing via reducing DNMT1 and H3K27me3 expressions. MiR-21 inhibition and miR-200a/b expression triggered by miR-340 ultimately cooperated in the TNBC progression.
Keywords: miR-340, EZH2, breast cancer, progression, miRNAs.