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Metalloproteinases 2 and -9 activity during promotion and progression stages of rat liver carcinogenesis

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Abstract

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.

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References

  • 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 80:939–944

    PubMed  CAS  Google 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 389–427

    Google Scholar 

  • Bitsch A, Hadjiolov N, Klöhn P-C, Bergmann O, Zwirner-Baier I, Neumann HG (2000) Dose response of early effects related to tumor promotion of 2-acetylaminofluorene. Toxicol Sci 55:44–51. doi:10.1093/toxsci/55.1.44

    Article  PubMed  CAS  Google Scholar 

  • Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477:267–283

    PubMed  CAS  Google Scholar 

  • Caudroy S, Polette M, Nawrocki-Raby B, Cao J, Toole BP, Zucker S et al (2002) EMMPRIN-mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis 19:697–702. doi:10.1023/A:1021350718226

    Article  PubMed  CAS  Google Scholar 

  • Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253:269–285. doi:10.1023/A:1026028303196

    Article  PubMed  CAS  Google 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

    Article  PubMed  CAS  Google Scholar 

  • Farber E, Sarma DS (1987) Hepatocarcinogenesis: a dynamic cellular perspective. Lab Investig 56:4–22

    PubMed  CAS  Google Scholar 

  • Foda HD, Zucker S (2001) Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis. Drug Discov Today 6:478–482. doi:10.1016/S1359-6446(01)01752-4

    Article  PubMed  CAS  Google Scholar 

  • Gao Y, Zhang Z, Jiang Z-S, Fang SG, Sun EW, Wang Y et al (2002) Dynamic changes of matrix metalloproteinases in rat liver during the development of diethylnitrosamine-induced hepatocarcinoma. Di Yi Jun Yi Da Xue Xue Bao 22:865–868

    PubMed  CAS  Google Scholar 

  • Gianelli G, Quaranta V, Antonaci S (2003) Tissue remodelling in liver diseases. Histol Histopathol 18:1267–1274

    Google Scholar 

  • Gulbis B, Alexandre K, Galand P (1993) Quantitative and/or qualitative changes in the p21-H-ras post-translational products in regenerating liver and during hepatocarcinogenesis. Int J Cancer 55:837–840. doi:10.1002/ijc.2910550524

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa R, Ito N (1994) Hepatocarcinogenesis in the rat. In: Waalkes MP, Ward JM (eds) Carcinogenesis. Raven Press Ltd, New York, pp 39–65

    Google Scholar 

  • Imaida K, Tatematsu M, Kato T, Tsuda H, Ito N (1989) Advantages and limitations of stereological estimation of placental glutathione S-transferase-positive rat liver cell foci by computerized three-dimensional reconstruction. Jpn J Cancer Res 80:326–330

    PubMed  CAS  Google Scholar 

  • Kaneyoshi T, Nakatsukasa H, Higashi T, Fujiwara K, Naito I, Nouso K et al (2001) Actual invasive potential of human hepatocellular carcinoma revealed by in situ gelatin zymography. Clin Cancer Res 7:4027–4032

    PubMed  CAS  Google Scholar 

  • Kim T-H, Mars WM, Stolz DB, Michalopoulos GK (2000) Expression and activation of pro-MMP-2 and pro-MMP-9 during rat liver regeneration. Hepatology 31:75–82. doi:10.1002/hep.510310114

    Article  PubMed  CAS  Google 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 113:443–453

    Google 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

    Article  PubMed  CAS  Google Scholar 

  • Libbrecht L, Desmet V, Roskams T (2005) Preneoplastic lesions in human hepatocarcinogenesis. Liver Int 25:16–27. doi:10.1111/j.1478-3231.2005.01016.x

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Hernandez A, Amenta PS (1993) The hepatic extracellular matrix I. Components and distribution in normal liver. Virchows Arch A Pathol Anat Histopathol 423:1–11. doi:10.1007/BF01606425

    Article  PubMed  CAS  Google Scholar 

  • Pascale RM, Simile MM, De Miglio MR, Muroni MR, Calvisi DF, Asara G, Casabona D et al (2002) Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. Hepatology 35:1341–1350. doi:10.1053/jhep.2002.33682

    Article  PubMed  CAS  Google Scholar 

  • Pinheiro F, Faria RR, de Camargo JL, Spinardi-Barbisan ALT, da Eira AF, Barbisan LF (2003) Chemoprevention of preneoplastic liver foci development by dietary mushroom Agaricus blazei Murrill in the rat. Food Chem Toxicol 41:1543–1550. doi:10.1016/S0278-6915(03)00171-6

    Article  PubMed  CAS  Google 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

    Article  PubMed  Google Scholar 

  • Pitot HC (2001) Pathways of progression in hepatocarcinogenesis. Lancet 358:859–860. doi:10.1016/S0140-6736(01)06038-X

    Article  PubMed  CAS  Google Scholar 

  • Ra HJ, Parks WC (2007) Control of matrix metalloproteinase catalytic activity. Matrix Biol 26:587–596. doi:10.1016/j.matbio.2007.07.001

    Article  PubMed  CAS  Google Scholar 

  • Ramaiah SK (2007) A toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters. Food Chem Toxicol 45:1551–1557. doi:10.1016/j.fct.2007.06.007

    Article  PubMed  CAS  Google Scholar 

  • Sell S, Dunsford NA (1989) Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol 134:1347–1363

    PubMed  CAS  Google Scholar 

  • Su Q, Bannasch P (2003) Relevance of hepatic preneoplasia for human hepatocarcinogenesis. Toxicol Pathol 31:126–133. doi:10.1080/01926230309732

    Article  PubMed  Google Scholar 

  • Tiwawech D, Hasegawa R, Kurata Y, Tatematsu M, Shibata MA, Thamavit W et al (1991) Dose-dependent effects of 2-acetylaminofluorene on hepatic foci development and cell proliferation in rats. Carcinogenesis 12:985–990. doi:10.1093/carcin/12.6.985

    Article  PubMed  CAS  Google Scholar 

  • Verna L, Whysner J, Williams GM (1996a) 2-acetylaminofluorene mechanistic data and risk assessment: DNA reactivity, enhanced cell proliferation and tumor initiation. Pharmacol Ther 71:83–105. doi:10.1016/0163-7258(96)00063-0

    Article  PubMed  CAS  Google Scholar 

  • Verna L, Whysner J, Williams GM (1996b) N-Nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity and tumor initiation. Pharmacol Ther 71:57–81. doi:10.1016/0163-7258(96)00062-9

    Article  PubMed  CAS  Google Scholar 

  • Vihinen P, Ala-Aho R, Kähäri V-M (2005) Matrix metalloproteinases as therapeutic targets in cancer. Curr Cancer Drug Targets 5:203–220. doi:10.2174/1568009053765799

    Article  PubMed  CAS  Google Scholar 

  • Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function and biochemistry. Circ Res 92:827–839. doi:10.1161/01.RES.0000070112.80711.3D

    Article  PubMed  CAS  Google Scholar 

  • Watanabe T, Nijoka M, Hozawa S, Kameyama K, Hayashi T, Arai M et al (2000) Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachloride. J Hepatol 33:224–235. doi:10.1016/S0168-8278(00)80363-3

    Article  PubMed  CAS  Google 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) 226:799–803

    CAS  Google Scholar 

  • Xu GF, Pt Li, Wang XY, Jia X, Tian DL, Jiang LD et al (2004) Dynamic changes in the expression of matrix metalloproteinases and their inhibitors, TIMPs, during hepatic fibrosis induced by alcohol in rats. World J Gastroenterol 10:3621–3627

    PubMed  CAS  Google Scholar 

  • Yano T, Yamasaki H (2001) Regulation of cellular invasion and matrix metalloproteinase activity in HepG2 cell by connexin 26 transfection. Mol Carcinog 31:101–109. doi:10.1002/mc.1045

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by CAPES, FAPESP and TOXICAM. Kelly S. Furtado was recipient of a fellowship from CAPES.

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Authors and Affiliations

  1. School of Medicine, Department of Pathology, UNESP São Paulo State University, Botucatu, SP, 18618-000, Brazil

    Kelly Silva Furtado & Maria Aparecida Marchesan Rodrigues

  2. Department of Cell Biology, Institute of Cell Biology, UNICAMP, Campinas, SP, 13083-950, Brazil

    Paulo Wagner Pires

  3. Department of Morphology, Institute of Biosciences, UNESP São Paulo State University, Botucatu, SP, 18618-000, Brazil

    Kelly Silva Furtado, Luis Antonio Justulin Jr., Sergio Luis Felisbino & Luis Fernando Barbisan

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  1. Kelly Silva Furtado
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  2. Paulo Wagner Pires
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  3. Luis Antonio Justulin Jr.
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  4. Maria Aparecida Marchesan Rodrigues
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  5. Sergio Luis Felisbino
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Correspondence to Luis Fernando Barbisan.

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Furtado, K.S., Pires, P.W., Justulin, L.A. et al. Metalloproteinases 2 and -9 activity during promotion and progression stages of rat liver carcinogenesis. J Mol Hist 40, 1–11 (2009). https://doi.org/10.1007/s10735-008-9206-x

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  • DOI: https://doi.org/10.1007/s10735-008-9206-x

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