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

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.

MnSOD Promotes Tumor Invasion via Upregulation of FoxM1–MMP2 Axis and Related with Poor Survival and Relapse in Lung Adenocarcinomas

“…Another report showed that MMP2 transcription was directly upregulated by FoxM1 and that the invasion of glioma cells was enhanced by FoxM1-induced MMP2 expression (30). In the present study, MMP2 expression was markedly decreased in FoxM1-knockdown cells (Fig.…”

“…However, FoxM1 also promotes the MMP2 expression that is associated with enhanced invasion by glioma cells (30). On the basis of the available evidence, we hypothesized that MnSOD might upregulate FoxM1 transcription, thereby promoting tumor aggressiveness via increased MMP2 expression.…”

“…FoxM1 is a known transcriptional factor that upregulates MMP2 expression (30). We hypothesized that MnSOD may increase FoxM1 expression and thereby lead to upregulation of MMP2 expression.…”

Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4

“…In addition, characteristic features of malignant glioma are its elevated cell motility and invasion which are currently known to be regulated by various molecules such as extracellular matrix, integrins, matrix metalloproteinases, growth factor receptors, focal adhesion kinases, PI-3 kinase, small GTPase, and transcription factors [15][16][17].…”

Expression of FLJ10540 is correlated with aggressiveness of oral cavity squamous cell carcinoma by stimulating cell migration and invasion through increased FOXM1 and MMP-2 activity

“…The elevated expression of the MMP-2 immunoreactive protein is correlated with a poor prognosis in OCSCC (Ruokolainen et al, 2004;Gao et al, 2005;Patel et al, 2007). In addition, MMP-2 expression could be regulated by several transcription factors, including YB-1 (Mertens et al, 1997), Sp1 (Qin et al, 1999), p53 (Bian and Sun, 1997), Stat3 (Xie et al, 2004) and FOXM1 (Dai et al, 2007); however, the molecular mechanisms by which MMP-2 is activated and controls tumor metastasis in OCSCC remain elusive.…”