Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells

B. Dai, S. H. Kang, W. Gong, M. Liu, K. D. Aldape, R. Sawaya, S. Huang

    Research output: Contribution to journalArticlepeer-review

    150 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)6212-6219
    Number of pages8
    JournalOncogene
    Volume26
    Issue number42
    DOIs
    Publication statusPublished - 2007 Sep 13

    Keywords

    • FoxM1B
    • Glioma
    • Invasion
    • MMP-2

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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