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

Kirstin Meyer*, Ju Seong Lee, Patricia A. Dyck, Wen Qing Cao, M. Sambasiva Rao, Snorri S. Thorgeirsson, Janardan K. Reddy

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

54 Scopus citations

Abstract

By using cDNA microarrays, we studied the expression profiles of 26 hepatocellular carcinomas (HCC) 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 α (PPARα) by the unmetabolized substrates of AOX, which serve as natural PPARα ligands. We then compared the AOX-/- liver tumor expression profiles with those induced by ciprofibrate, a non-genotoxic peroxisome proliferator, or by the genotoxic carcinogen diethylnitrosamine (DENA) to discern differences in gene expression patterns that may predict or distinguish PPARα-mediated liver tumors from genotoxically derived tumors. Our results show that HCCs 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 PPARα and PPARα-regulated genes in liver, including those participating in lipid catabolism, as key factors in the development of HCC 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 identified previously as PPARα regulated, such as CD36, lymphocyte antigen 6 complex locus (Ly-6D), and C3f. We found a panel of 12 genes upregulated in all three classes of liver tumors, namely AOX-/-, ciprofibrate-induced and DENA-induced. These include an uncharacterized RIKEN cDNA, lipocalin 2, insulin-like growth factor-binding protein 1, Ly-6D and CD63 among others. In conclusion, these results identify distinguishing features between non-genotoxic and genotoxic carcinogen derived liver tumors as well as genes that are upregulated in both types and suggest that RIKEN cDNA, Ly-6D and lipocalin 2 in particular appear to be desirable molecular markers for further study in liver carcinogenesis and progression.

Original languageEnglish (US)
Pages (from-to)975-984
Number of pages10
JournalCarcinogenesis
Volume24
Issue number5
DOIs
StatePublished - May 1 2003

Funding

This work was supported by National Institutes of Health Grants GM 23750 (to J.K.R.) and CA 84472 (to M.S.R.).

ASJC Scopus subject areas

  • Cancer Research

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