Abstract
We recently showed that FoxM1 is overexpressed in human glioblastomas and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly invasive glioblastoma multiforme (GBM) in nude mice. However, the molecular mechanisms by which FoxM1 enhances glioma invasion are unknown. In this study, we found that FoxM1 overexpression increased matrix metalloproteinase (MMP)-2 expression in glioma cells, whereas blockade of FoxM1 expression suppressed MMP-2 expression. Transfection of FoxM1 into glioma cells directly activated the MMP-2 promoter, whereas inhibition of FoxM1 expression by FoxM1-siRNA suppressed its activation. We identified a FoxM1-binding site in the MMP-2 promoter and demonstrated that FoxM1 protein bound directly to it. Mutation of this FoxM1-binding site significantly attenuated MMP-2 promoter activity. Furthermore, FoxM1 overexpression increased the invasiveness of glioma cells, whereas inhibition of FoxM1 expression suppressed the invasiveness of GBM cells. Inhibition of MMP-2 by a specific MMP-2 inhibitor reversed the invasive phenotype of glioma cells overexpressing FoxM1. Finally, immunohistochemical analysis of 45 human GBM specimens showed a significant correlation between FoxM1 overexpression and elevated MMP-2 expression. Collectively, these findings provide evidence that FoxM1 contributes to glioma progression by enhancing MMP-2 gene transcription and thus tumor-cell invasion.
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Acknowledgements
We thank Don Norwood and Christine Wogan for editorial comments. This work was supported in part by a NCI Grant R01-CA116528 (to SH), a Research Grant from the Brain Tumor Society (to SH), the Anthony Bullock III Brain Tumor Research Fund (to RS) and Cancer Center Support Grant CA 16672 from the NCI.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Dai, B., Kang, SH., Gong, W. et al. Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. Oncogene 26, 6212–6219 (2007). https://doi.org/10.1038/sj.onc.1210443
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DOI: https://doi.org/10.1038/sj.onc.1210443
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