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J. Biol. Chem., Vol. 282, Issue 30, 21998-22010, July 27, 2007

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MMP25 (MT6-MMP) Is Highly Expressed in Human Colon Cancer, Promotes Tumor Growth, and Exhibits Unique Biochemical Properties^*

Qing Sun, Christopher R. Weber, Anjum Sohail, M. Margarida Bernardo, Marta Toth^¶, Huiren Zhao, Jerrold R. Turner, and Rafael Fridman¹

From the Department of Pathology and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, the Department of Pathology, University of Chicago, Chicago, Illinois 60637, and the ^¶Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556

MMP25 (MT6-MMP) is one of the two glycosylphosphatidylinositol-anchored matrix metalloproteinases (MMPs) that have been suggested to play a role in pericellular proteolysis. However, its role in cancer is unknown, and its biochemical properties are not well established. Here we found a marked increase in MT6-MMP expression within in situ dysplasia and invasive cancer in 61 samples of human colon cancer. Expression of MT6-MMP in HCT-116 human colon cancer cells promoted tumori-genesis in nude mice. Histologically, the MT6-MMP-expressing tumors demonstrated an infiltrative leading edge in contrast to a rounded leading edge in vector control tumors. Biochemical and biosynthesis analyses revealed that MT6-MMP displayed on the cell surface exists as a major form of 120 kDa that likely represents enzyme homodimers linked by disulfide bonds. Upon reduction, a single 57-kDa active MT6-MMP was detected. Interestingly, neither membrane-anchored nor phosphatidylinositol-specific phospholipase C-released MT6-MMPs were found to be associated with tissue inhibitor of metalloproteinases (TIMPs) and did not activate pro-gelatinases (pro-MMP-2 and pro-MMP-9) even in the presence of exogenous TIMP-2 or TIMP-1. A catalytic domain of MT6-MMP was inhibited preferentially by TIMP-1 (K_i = 0.2 nM) over TIMP-2 (K_i = 2.0 nM), because of a slower association rate. These results show that MT6-MMP may play a role in colon cancer and exhibit unique biochemical and structural properties that may regulate proteolytic function at the cell surface.

Received for publication, February 28, 2007 , and in revised form, May 1, 2007.

^* This work was supported by National Institutes of Health Grants RO1 CA-61986-11, CA-100475 (to R. F.), R01 DK61931, and R01 DK68271 (to J. R. T.) and University of Chicago Cancer Research Center Grant P30 CA14599. 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. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Pathology, Wayne State University, 540 E. Canfield Ave., Detroit, MI 48201. Tel.: 313-577-1218; Fax: 313-577-8180; E-mail: rfridman{at}med.wayne.edu.

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				H. Zhao, A. Sohail, Q. Sun, Q. Shi, S. Kim, S. Mobashery, and R. Fridman Identification and Role of the Homodimerization Interface of the Glycosylphosphatidylinositol-anchored Membrane Type 6 Matrix Metalloproteinase (MMP25) J. Biol. Chem., December 12, 2008; 283(50): 35023 - 35032. [Abstract] [Full Text] [PDF]