Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer.
OBJECTIVE
The balance between local levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases is believed to play a key role in tumor invasion and metastases. Because tissue inhibitor of metalloproteinase-3 suppresses tumorigenicity and tumor invasion in vitro, the aim of this study was to determine its expression in human colorectal cancer.


METHODS
Thirty-nine human colorectal cancer specimens, three adenomas, and matched normal adjacent mucosa from 39 colorectal cancer patients were analyzed. Tissue inhibitor of metalloproteinase-3 ribonucleic acid and protein expression were analyzed by Northern blot hybridization and Western blot analysis, respectively. The cellular localizations of tissue inhibitor of metalloproteinase-3 ribonucleic acid and protein were determined by in situ hybridization and immunolocalization.


RESULTS
Tissue inhibitor of metalloproteinase-3 ribonucleic acid expression was increased in colorectal cancer compared with paired normal mucosa. In contrast, tissue inhibitor of metalloproteinase-3 protein level was higher in normal mucosa than in the corresponding colorectal cancer. In addition, tissue inhibitor of metalloproteinase-3 protein levels progressively decreased with advancing colorectal cancer stages. Tissue inhibitor of metalloproteinase-3 protein tumor to normal mucosa ratio was 0.74 +/- 0.12, 0.51 +/- 0.18, 0.48 +/- 0.12, and 0.45 +/- 0.2 for Dukes A (n = 8), B (n = 9), C (n = 9), and D (n = 13) stages, respectively. Both tissue inhibitor of metalloproteinase-3 messenger ribonucleic acid and protein were located predominantly within spindle-shaped and round stromal cells. Furthermore, in colonic epithelium, tissue inhibitor of metalloproteinase-3 and type IV collagen protein were similarly concentrated in the basal region.


CONCLUSIONS
These data provide the first detailed description of the cellular expression of tissue inhibitor of metalloproteinase-3 in colorectal cancer and identify it as a basement membrane-associated protein. This is an important observation, because the presence of tissue inhibitor of metalloproteinase-3 protein near the basement membrane supports its role in preventing proteolytic degradation, angiogenesis, and apoptosis.
Zeng
Z
Z
Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Sun
Y
Y
Shu
W
W
Guillem
J G
JG
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001485:Basement Membrane / Q000737:chemistry* / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011480:Protease Inhibitors / Q000032:analysis*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis / Q000096:biosynthesis*
D011480:Protease Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3