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Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells
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Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells
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Journal Article
Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells
2007
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
Subject
/ Biological and medical sciences
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ Forkhead Transcription Factors - biosynthesis
/ Forkhead Transcription Factors - genetics
/ Forkhead Transcription Factors - physiology
/ Fundamental and applied biological sciences. Psychology
/ Genetics
/ Glioma
/ Gliomas
/ Humans
/ Kinases
/ Matrix Metalloproteinase 2 - biosynthesis
/ Matrix Metalloproteinase 2 - genetics
/ Medicine
/ Molecular and cellular biology
/ Oncology
/ Proteins
/ Rodents
/ siRNA
/ Transcription, Genetic - physiology
/ Transcription. Transcription factor. Splicing. Rna processing
