Journal
JOURNAL OF HEPATOLOGY
Volume 46, Issue 1, Pages 69-76Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2006.06.015
Keywords
hepatocellular carcinoma; metastasis; metalloproteinase; pravastatin
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Background/Aims: Statins have beneficial effects in early pre-clinical models of hepatocellular carcinoma (HCC). Our aim was to test the efficacy of pravastatin on the progression of established HCC in rat, and to study its mechanisms. Methods: HCC was induced with diethylnitrosamine and N-nitrosomorpholine. After 14 weeks, all rats developed HCC and then received pravastatin or its solvent for 10 weeks (10 rats/group). Results: Liver tumor mass was lower in pravastatin group (PG) than control group (CG), as estimated from the number of liver tumors (p < 0.004) and the liver weight/body weight ratio (p < 0.04). Every CG rat surviving at 24 weeks (4/4) had lung metastasis, against only 5/8 in PG. Moreover, the percentage of lung surface occupied by metastasis was 10-fold smaller in PG than CG (p < 0.016). Pravastatin decreased liver matrix metalloproteinase (MMP)-9 activity and mostly suppressed MMP-2 activation (p < 0.004), likely because it decreased expression of MMP-14 and tissue inhibitor of matrix metalloproteinases-2 (p < 0.01), required for MMP-2 activation. Conclusions: Pravastatin reduces progression and limits metastatic diffusion of established HCC. This could be linked to the decreased MMP activity. These results, obtained in a very aggressive HCC model, further suggest the potential benefit of statins in human HCC. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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