Abstract
Purpose
BMP-6, which belongs to the TGF-β superfamily, is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis. Our recent research has implied that BMP-6 may suppress breast cancer metastasis. In the present study, we extended to elucidate the molecular mechanism by which BMP-6 exerts its anti-tumorigenic effect.
Methods
The Boyden chamber assay was used to examine the ability of BMP-6 and HO-1 in MCF-7 malignant progress. RT-PCR, western blot, luciferase assay, and quantitative CHIP were used to determine the potential mechanism and signaling pathways by which BMP-6 and HO-1 function as anti-metastatic factors in MCF-7 cells.
Results
The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MCF-7 cells, which effect was significantly deprived by knockdown of HO-1. We further demonstrated that BMP-6 treatment resulted in an activation of HO-1 transcription through the recruitment of Smad1/5 to the Smad-responsive element on its promoter. In addition, BMP-6-induced up-regulation of HO-1 exhibited an inhibitory effect on MMP-9 secretion in a paracrine action in MCF-7 cells. Overexpression of BMP-6 and HO-1 synergistically suppressed MMP-9 transcription, which effect was specifically mediated via the MAPK/p38/AP-1 signaling. However, blockade of HO-1 using ZnPPIX totally abolished BMP-6-regulated MMP-9 activation in MCF-7 cells.
Conclusions
These observations suggest a novel role of BMP-6/HO-1 cascade to relieve breast cancer metastasis by regulating the secretion of growth factors in tumor microenvironment.
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Acknowledgments
This work is supported by grants from the National Nature Science Foundation of China (No. 81072153) and from Tianjin Natural Science Foundation (No. 09JCYBJC09100) to S. Yang.
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The authors declare that we have no conflict of interest.
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Wang, C., Hu, F., Guo, S. et al. BMP-6 inhibits MMP-9 expression by regulating heme oxygenase-1 in MCF-7 breast cancer cells. J Cancer Res Clin Oncol 137, 985–995 (2011). https://doi.org/10.1007/s00432-010-0963-z
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DOI: https://doi.org/10.1007/s00432-010-0963-z