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J Cancer. 2017 Sep 2;8(15):3037-3048. doi: 10.7150/jca.19315. eCollection 2017.

MiR-340 Inhibits Triple-Negative Breast Cancer Progression by Reversing EZH2 Mediated miRNAs Dysregulated Expressions.

Shi Z1,2,3, Li Y1,2,3, Qian X4, Hu Y1,2,3, Liu J1,2,3, Zhang S1,2,3, Zhang J1,2,3.

Author information

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.

Abstract

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:

EZH2; breast cancer; miR-340; miRNAs.; progression

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

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