BMP-6 inhibits MMP-9 expression by regulating heme oxygenase-1 in MCF-7 breast cancer cells

• Published in: Journal of cancer research and clinical oncology 2011-06, Vol.137 (6), p.985-995
• Main Authors: Wang, Chuan, Hu, Fen, Guo, Shaocong, Mi, Dong, Shen, Wenwen, Zhang, Jie, Qiao, Yuhuan, Zhu, Tianhui, Yang, Shuang
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Bone Morphogenetic Protein 6 - physiology; Breast cancer; Breast Neoplasms - pathology; Cancer Research; Cell Line, Tumor; Female; Gynecology. Andrology. Obstetrics; Hematology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - physiology; Humans; Internal Medicine; Mammary gland diseases; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase Inhibitors; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Neoplasm Metastasis - prevention & control; Oncology; Original Paper; p38 Mitogen-Activated Protein Kinases - physiology; Pharmacology. Drug treatments; Proteins; Signal Transduction; Smad Proteins - physiology; Transcription Factor AP-1 - physiology; Tumors
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-010-0963-z

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.