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Cell Res. 2009 Apr;19(4):487-96. doi: 10.1038/cr.2009.34.

BMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1.

Author information

1
Laboratory of Medical Molecular Biology, Medical College of Nankai University, 94 Weijin Road, Tianjin 300071, China.

Abstract

MicroRNAs (miRNAs), which are small noncoding RNA molecules, play important roles in the post-transcriptional regulation process. The microRNA-21 gene (miR-21) has been reported to be highly expressed in various solid tumors, including breast cancer. Bone morphogenetic protein-6 (BMP-6) has been identified as an inhibitor of breast cancer epithelial-mesenchymal transition (EMT) through rescuing E-cadherin expression. We initiated experiments to identify the relationships between miR-21 and BMP-6 in breast cancer progression. Real-time PCR analysis showed that miR-21 expression was very high in MDA-MB-231 cells that expressed little BMP-6. A reverse correlation between BMP-6 and miR-21 was also determined in breast cancer tissue samples. Moreover, BMP-6 inhibited miR-21 transcription in MDA-MB-231 cells. In order to investigate how BMP-6 inhibited the miR-21 promoter (miPPR-21), we constructed a series of miPPR-21 reporters. Luciferase assay results indicated that BMP-6 inhibited miPPR-21 activity through the E2-box and AP-1-binding sites. We also demonstrated that both deltaEF1 and TPA induced miR-21 expression. Using site-directed mutation and CHIP assay, we found that deltaEF1 induced miPPR-21 activity by binding to the E2-box on miPPR-21. Moreover, TPA triggered miPPR-21 activity through the AP-1 binding sites. BMP-6 treatment significantly reduced the binding of these factors to miPPR-21 by decreasing the expression of deltaEF1 and c-Fos/c-Jun. We also demonstrated that BMP-6-induced downregulation of miR-21 modified the activity of PDCD4 3'UTR and inhibited MDA-MB-231 cell invasion. deltaEF1 overexpression and TPA induction blocked this inhibitory effect of BMP-6. In conclusion, BMP-6-induced inhibition of miR-21 suggests that BMP-6 may function as an anti-metastasis factor by a mechanism involving transcriptional repression of miR-21 in breast cancer.

PMID:
19308091
DOI:
10.1038/cr.2009.34
[Indexed for MEDLINE]

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