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

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

Research output: Contribution to journalArticle

135 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
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 2
Glioma
Glioblastoma
Binding Sites
Matrix Metalloproteinase Inhibitors
Astrocytoma
Nude Mice
Small Interfering RNA
Transfection
Phenotype
Mutation

Keywords

  • FoxM1B
  • Glioma
  • Invasion
  • MMP-2

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. / Dai, B.; Kang, Shin-Hyuk; Gong, W.; Liu, M.; Aldape, K. D.; Sawaya, R.; Huang, S.

In: Oncogene, Vol. 26, No. 42, 13.09.2007, p. 6212-6219.

Research output: Contribution to journalArticle

Dai, B. ; Kang, Shin-Hyuk ; Gong, W. ; Liu, M. ; Aldape, K. D. ; Sawaya, R. ; Huang, S. / Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. In: Oncogene. 2007 ; Vol. 26, No. 42. pp. 6212-6219.
@article{d76b241aa97443448074050aeb067f63,
title = "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.",
keywords = "FoxM1B, Glioma, Invasion, MMP-2",
author = "B. Dai and Shin-Hyuk Kang and W. Gong and M. Liu and Aldape, {K. D.} and R. Sawaya and S. Huang",
year = "2007",
month = "9",
day = "13",
doi = "10.1038/sj.onc.1210443",
language = "English",
volume = "26",
pages = "6212--6219",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "42",

}

TY - JOUR

T1 - Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells

AU - Dai, B.

AU - Kang, Shin-Hyuk

AU - Gong, W.

AU - Liu, M.

AU - Aldape, K. D.

AU - Sawaya, R.

AU - Huang, S.

PY - 2007/9/13

Y1 - 2007/9/13

N2 - 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.

AB - 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.

KW - FoxM1B

KW - Glioma

KW - Invasion

KW - MMP-2

UR - http://www.scopus.com/inward/record.url?scp=34548558343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548558343&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1210443

DO - 10.1038/sj.onc.1210443

M3 - Article

C2 - 17404569

AN - SCOPUS:34548558343

VL - 26

SP - 6212

EP - 6219

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 42

ER -