Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine.
In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, and membrane-type 1 MMP (MT1-MMP) and MT2-MMP in ductal lesions in a rapid-production model for pancreatic duct carcinomas (PCs) in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) and in subcutaneous transplantable tumors of hamster pancreatic duct carcinoma (HPDs) was investigated. Northern analysis revealed MMP-2, MMP-9, TIMP-2 and MT1-MMP mRNAs to be overexpressed in PCs. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in both of primary and HPD tumors, the MT1-MMP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001). In our rapid production model, 0.1 and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that overexpression of MMP-2, TIMP-2 and MT1-MMP, and cell surface activation of proMMP-2 by MT1-MMP, are involved in the development of PCs, and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. OPB-3206 may be a candidate chemopreventive agent for pancreatic ductal adenocarcinomas.
Iki
K
K
Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-0813, Japan.
Tsutsumi
M
M
Kido
A
A
Sakitani
H
H
Takahama
M
M
Yoshimoto
M
M
Motoyama
M
M
Tatsumi
K
K
Tsunoda
T
T
Konishi
Y
Y
D000230:Adenocarcinoma / Q000139:chemically induced / Q000201:enzymology*; D000818:Animals; D015153:Blotting, Western; D017364:Collagenases / Q000096:biosynthesis; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000096:biosynthesis* / Q000378:metabolism*; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000378:metabolism*; D009602:Nitrosamines / Q000037:antagonists & inhibitors; D010183:Pancreatic Ducts; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*
D004792:Enzyme Precursors; D009602:Nitrosamines; D011480:Protease Inhibitors; D015363:Quinolones; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; C013622:nitrosobis(2-oxopropyl)amine; D005780:Gelatin; C119316:OPB 3206; D017364:Collagenases; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9