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.

Abstract

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.

• Authors: K Iki, M Tsutsumi, A Kido, H Sakitani, M Takahama, M Yoshimoto, M Motoyama, K Tatsumi, T Tsunoda, Y Konishi
• Journal: Carcinogenesis (Carcinogenesis) Vol. 20 Issue 7 Pg. 1323-9 (Jul 1999) ISSN: 0143-3334 [Print] England
• PMID: 10383907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Precursors
• Nitrosamines
• Protease Inhibitors
• Quinolones
• RNA, Messenger
• Tissue Inhibitor of Metalloproteinase-2
• nitrosobis(2-oxopropyl)amine
• Gelatin
• OPB 3206
• Collagenases
• Gelatinases
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• progelatinase
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Adenocarcinoma (chemically induced, enzymology)
• Animals
• Blotting, Western
• Collagenases (biosynthesis)
• Cricetinae
• Enzyme Activation (drug effects)
• Enzyme Precursors (metabolism)
• Female
• Gelatin (metabolism)
• Gelatinases (biosynthesis, metabolism)
• Immunohistochemistry
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (biosynthesis, metabolism)
• Nitrosamines (antagonists & inhibitors)
• Pancreatic Ducts
• Pancreatic Neoplasms (chemically induced, enzymology)
• Protease Inhibitors (pharmacology)
• Quinolones (pharmacology)
• RNA, Messenger (biosynthesis)
• Tissue Inhibitor of Metalloproteinase-2 (biosynthesis)