MMP25 (MT6-MMP) is highly expressed in human colon cancer, promotes tumor growth, and exhibits unique biochemical properties

J Biol Chem. 2007 Jul 27;282(30):21998-2010. doi: 10.1074/jbc.M701737200. Epub 2007 May 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma
  • Amino Acid Sequence
  • Animals
  • Catalytic Domain
  • Cell Division
  • Cell Line, Tumor
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / pathology
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / pathology
  • Epithelial Cells
  • GPI-Linked Proteins
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycosylphosphatidylinositols / metabolism
  • Haplorhini
  • Humans
  • Matrix Metalloproteinases, Membrane-Associated / genetics*
  • Matrix Metalloproteinases, Membrane-Associated / metabolism
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / pharmacology
  • Tissue Inhibitor of Metalloproteinase-2 / pharmacology
  • Transfection

Substances

  • GPI-Linked Proteins
  • Glycosylphosphatidylinositols
  • Neoplasm Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinases, Membrane-Associated
  • matrix metalloproteinase 25