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Molecular and Cellular Biology, October 2005, p. 8581-8591, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8581-8591.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Runx2 Osteogenic Transcription Factor Regulates Matrix Metalloproteinase 9 in Bone Metastatic Cancer Cells and Controls Cell Invasion

Jitesh Pratap,1,3 Amjad Javed,1,3 Lucia R. Languino,2,3 Andre J. van Wijnen,1,3 Janet L. Stein,1,3 Gary S. Stein,1,3 and Jane B. Lian1,3*

Departments of Cell Biology,1 Cancer Biology,2 Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 016553

Received 7 January 2005/ Returned for modification 8 February 2005/ Accepted 20 June 2005

The Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.

* Corresponding author. Mailing address: Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: (508) 856-5625. Fax: (508) 856-6800. E-mail: jane.lian{at}umassmed.edu.

Molecular and Cellular Biology, October 2005, p. 8581-8591, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8581-8591.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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