Metalloproteinases 2 and -9 activity during promotion and progression stages of rat liver carcinogenesis
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Activity of metalloproteinases 2 and 9 (MMP-2 and 9) during promotion and progression of rat liver carcinogenesis was investigated in a modified resistant hepatocyte model. Development of preneoplastic liver lesions positive for glutathione S-transferase 7-7-(GST-P 7-7-positive PNL) and tumors besides hepatocytes positive for proliferating cell nuclear antigen (PCNA) were quantified and compared to MMP-2 and-9 activity using gelatin zymography. Marked increases in GST-P 7-7-positive PNL development, PCNA labeling indices, MMP-2 (pro, intermediate and active forms) and pro-MMP-9 activity were observed after proliferative stimulus induced by 2-acetylaminofluorene (2-AAF) exposure cycles. After 2-AAF withdrawal, increase in MMP-2 activity was detected only in neoplastic mixed lesions, whereas active MMP-9 was increased in both PLN and neoplastic tissues. Our findings suggest that MMP-2 may be associated with proliferative events induced by 2-AAF rather than with selective growth of PNL and that MMP-9 could be associated with progression of PNL and neoplastic mixed lesions.
KeywordsRat liver carcinogenesis Resistant hepatocyte model Metalloproteinases Preneoplastic and neoplastic lesions
This work was supported by CAPES, FAPESP and TOXICAM. Kelly S. Furtado was recipient of a fellowship from CAPES.
- Asamoto M, Tsuda H, Kagawa M, de Camargo JL, Ito N, Nagase S (1989) Strain differences in susceptibility to 2-acetylaminofluorene and phenobarbital promotion of rat hepatocarcinogenesis in a medium-term assay system: quantitation of glutathione S-transferase P-positive foci development. Jpn J Cancer Res 80:939–944PubMedGoogle Scholar
- Bannasch P, Zerban H (1992) Predictive value of hepatic preneoplastic lesions as indicators of carcinogenic response. In: Vainio H, Magee PN, McGregor DB, McMichal AJ (eds) Mechanism of carcinogenesis in risk identification, vol 116. IARC Sci Publ, Lyon, pp 389–427Google Scholar
- Denda A, Kitayama W, Murata A, Kishida H, Sasaki Y, Kusuoka O, Tsujiuchi T et al (2002) Increased expression of cyclooxygenase-2 protein during rat hepatocarcinogenesis caused by a choline-deficient, l-amino acid-defined diet and chemopreventive efficacy of a specific inhibitor, nimesulide. Carcinogenesis 23:245–256. doi: 10.1093/carcin/23.2.245 PubMedCrossRefGoogle Scholar
- Gianelli G, Quaranta V, Antonaci S (2003) Tissue remodelling in liver diseases. Histol Histopathol 18:1267–1274Google Scholar
- Hasegawa R, Ito N (1994) Hepatocarcinogenesis in the rat. In: Waalkes MP, Ward JM (eds) Carcinogenesis. Raven Press Ltd, New York, pp 39–65Google Scholar
- Kinnitel T, Mehde M, Grundmann A, Saile B, Scharf JG, Ramadori G (2000) Expression of matrix metalloproteinases and their inhibitors during hepatic tissue repair in the rat. Histochem Cell Biol 113:443–453Google Scholar
- Lee KW, Kim MS, Kang NJ, Kim DH, Surh YJ, Lee HJ et al (2006) H-Ras selectively up-regulates MMP-9 and COX-2 through activation of ERK1/2 and NF-kappaB: an implication for invasive phenotype in rat liver epithelial cells. Int J Cancer 119:1767–1775. doi: 10.1002/ijc.22056 PubMedCrossRefGoogle Scholar
- Pires PW, Furtado KS, Justulin LA Jr, Rodrigues MAM, Felisbino SL, Barbisan LF (2008) Chronic ethanol intake promotes double gluthatione S-transferase/transforming growth factor-α-positive hepatocellular lesions in male Wistar rats. Cancer Sci 99:221–228. doi: 10.1111/j.1349-7006.2007.00677.x PubMedCrossRefGoogle Scholar
- Wood GA, Archer MC (2001) Matrix metalloproteinases-2 and 9 do not play a role in the grotwth of preneoplastic liver lesions in F344 rats. Exp Biol Med (Maywood) 226:799–803Google Scholar