Carcinogenesis Advance Access published online on March 28, 2003
Carcinogenesis, doi:10.1093/carcin/bgg040
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Department of Pathology, Northwestern University, the Feinberg School of Medicine, Chicago, Illinois 60611-3008
* Corresponding author. E-mail: jkreddy{at}northwestern.edu.
Received 3 December 2002
; revised 27 January 2003
; accepted 28 February 2003
By using cDNA microarrays, we studied the expression profiles of 26 hepatocellular carcinomas developing spontaneously in peroxisomal fatty acyl-CoA oxidase null (AOX-/-) mice. The development of liver tumors in AOX-/- mice is due to sustained activation of peroxisome proliferator-activated receptor
Molecular profiling of hepatocellular carcinomas developing spontaneously in Acyl-CoA oxidase deficient mice: Comparison with liver tumors induced in wild type mice by a peroxisome proliferator and a genotoxic carcinogen
2 Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055
3 Center for Genetic Medicine, Northwestern University, the Feinberg School of Medicine, Chicago, Illinois 60611-3008
(PPAR) by the unmetabolized substrates of AOX, which serve as natural PPAR ligands. We then compared the AOX-/- liver tumor expression profiles with those induced by ciprofibrate, a nongenotoxic peroxisome proliferator, or by the genotoxic carcinogen diethylnitrosamine (DENA) to discern differences in gene expression patterns that may predict or distinguish PPAR mediated liver tumors from genotoxically derived tumors. Our results show that hepatocellular carcinomas developing in AOX-/- mice share a number of deregulated (up- or down-regulated) genes with ciprofibrate-induced liver tumors. The overall commonality of expression between AOX-/- and ciprofibrate-induced liver tumors but not with DENA-induced tumors strongly implicates the activation of PPAR and PPAR-regulated genes in liver, including those participating in lipid catabolism, as key factors in the development of hepatocellular carcinoma in AOX-/- and in ciprofibrate-treated mice. Northern blot analysis confirmed the differential expression of some of the genes identified in the present study, and also some genes previously identified as PPAR regulated, such as CD36, Ly-6D, RBP7, and C3f. We found a panel of 12 genes upregulated in all 3 classes of liver tumors, namely AOX-/-, ciprofibrate-induced and DENA induced. These include retinoid binding protein 7 (Rbp7), lipocalin 2, insulin like growth factor binding protein 1, Ly-6D, and CD63 among others. In conclusion, these results identify distinguishing features between nongenotoxic and genotoxic carcinogen derived liver tumors as well as genes which are upregulated in both types and suggest that RBP7, Ly-6D, and lipocalin 2 in particular appear to be desirable molecular markers for further study in liver carcinogenesis and progression.
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