BMP-6 inhibits MMP-9 expression by regulating heme oxygenase-1 in MCF-7 breast cancer cells.
OBJECTIVE
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.
Medical College of Nankai University, 94 Weijin Road, Tianjin 300071, China.
Chuan
C
Wang
Fen
F
Hu
Shaocong
S
Guo
Dong
D
Mi
Wenwen
W
Shen
Jie
J
Zhang
Yuhuan
Y
Qiao
Tianhui
T
Zhu
Shuang
S
Yang
D055418:Bone Morphogenetic Protein 6 / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D009362:Neoplasm Metastasis / Q000517:prevention & control; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D061965:Matrix Metalloproteinase Inhibitors; D051785:Smad Proteins; D018808:Transcription Factor AP-1; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9