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J. Biol. Chem., Vol. 283, Issue 10, 6232-6240, March 7, 2008

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Membrane Type 1 Matrix Metalloproteinase Induces Epithelial-to-Mesenchymal Transition in Prostate Cancer^*

Jian Cao¹, Christian Chiarelli, Omer Richman, Kevin Zarrabi, Pallavi Kozarekar, and Stanley Zucker

From the Department of Medicine, School of Medicine, Stony Brook University, Stony Brook, New York 11794 and the Department of Research, Veterans Affairs Medical Center, Northport, New York 11768

By mining DNA microarray data bases at GenBank^TM, we identified up-regulation of membrane type 1 matrix metalloproteinase (MT1-MMP) in human primary and metastatic prostate cancer specimens as compared with nonmalignant prostate tissues. To explore the role of up-regulated MT1-MMP in early stage cancer progression, we have employed a three-dimensional cell culture model. Minimally invasive human prostate cancer cells (LNCaP) were transfected with MT1-green fluorescent protein (GFP) chimeric cDNA as compared with GFP cDNA, and morphologic and phenotypic changes were characterized. GFP-expressing LNCaP cells formed multicellular spheroids with cuboidal-like epithelial morphology, whereas MT1-GFP-expressing cells displayed a fibroblast-like morphology and a scattered growth pattern in type I collagen gels. Cell morphologic changes were accompanied by decreased epithelial markers and enhanced mesenchymal markers, consistent with epithelial-to-mesenchymal transition. MT1-MMP-induced morphologic change and cell scattering were abrogated by target inhibition of either the catalytic domain or the hemopexin domain. We further demonstrated that MT1-MMP-induced phenotypic changes were dependent upon up-regulation of Wnt5a, which has been implicated in epithelial-to-mesenchymal transition. We conclude that MT1-MMP plays an important role in early cancer dissemination by converting epithelial cells to migratory mesenchymal-like cells.

Received for publication, July 13, 2007 , and in revised form, December 18, 2007.

^* This work was supported by National Institutes of Health Grant RO1CA11355301A1 and the Walk-for-Beauty Foundation (to J. C.), a Research Enhancement Award Program grant from the Department of Veterans Affairs, and Department of Defense Idea Award BC045521 (to S. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Medicine, Stony Brook University, Life Sciences Bldg., Rm. 004, Stony Brook, NY 11794. Tel.: 631-632-1815; E-mail: jian.cao{at}sunysb.edu.

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