Carcinogenesis, Vol. 20, No. 7, 1323-1329,
July 1999
© 1999 Oxford University Press
Carcinogenesis |
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
Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-0813,
1 Department of Gastroenterological Surgery, Kawasaki Medical University, 577 Matsusima, Kurashiki, Okayama 701-0192 and
2 Fuji Memorial Research Institute, Otsuka Pharmaceutical Co., Shiga, 1-11-1, Karasaki, Otsu, Shiga 520-01, Japan
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.
Abbreviations: BOP, N-nitrosobis(2-oxopropyl)amine; GAPDH, glyceraldehyde-3-phosphatase dehydrogenase; HPDs, subcutaneous transplantable tumors of hamster pancreatic duct carcinoma; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; PC, pancreatic duct adenocarcinoma; SSC, standard saline citrate; TIMP, tissue inhibitor of metalloproteinase.
3 To whom correspondence should be adressed Email: ykonishi{at}nmu-gw.cc.naramed-u.ac.jp
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