Balance between activation and inhibition of matrix metalloproteinase-2 (MMP-2) is altered in colorectal tumors compared to normal colonic epithelium.
Matrix metalloproteinase-2 (MMP-2) is overexpressed in human cancers and facilitates tumor growth and metastasis. It is synthesized as an inactive proenzyme that is activated by membrane-type matrix metalloproteinase-1 (MT1-MMP) and inhibited by tissue inhibitor of metalloproteinase-2 (TIMP-2). We hypothesized that there is an imbalance between the expression of TIMP-2 and the expression of MMP-2 and MT1-MMP that favors activation of MMP-2 in malignant colon tumors compared to normal colonic tissue. Specimens of colon tumors and of adjacent normal mucosa were obtained from 22 patients at the time of surgical resection. MMP-2, MT1-MMP, and TIMP-2 RNA transcripts were measured in each sample using a quantitative reverse transcriptase polymerase chain reaction assay. We observed that MMP-2 RNA levels were significantly elevated in tumors compared to normal tissue (P = 0.039). In addition, the TIMP-2:MMP-2 ratio was twofold lower (P = 0.001) and the TIMP-2:MT1-MMP ratio was 1.5-fold lower (P = 0.003) in tumors compared to normal mucosa. These results suggest that the balance between genes that activate and inhibit MMP-2 is shifted toward activation in colon tumors. The abnormal expression of gene products that regulate MMP-2 activity may be an important early step in the malignant transformation of colon cancer and may provide a useful target for new chemoprevention and adjuvant treatment strategies.
Dartmouth Medical School, Hanover, New Hampshire, USA.
Deborah L
DL
Ornstein
Kenneth H
KH
Cohn
D003106:Colon / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000201:enzymology*; D004789:Enzyme Activation; D004848:Epithelium / Q000201:enzymology; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012313:RNA / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D012313:RNA; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2