To clarify hepatocarcinogenesis by the heterocyclic amine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), we investigated the global expression of genes in rat liver. Rats were continuously fed MeIQx 100 ppm in their diet, and were sacrificed at weeks 4 and 16 for early time points, and week 104 for tumor sampling. Global expression analysis using oligonucleotide microarrays (Affimetrix Gene Chip, Rat Genome 230 2.0 Array) was carried out to detect altered genes in MeIQx-treated liver at 4 and 16 weeks (n=5, each), MeIQx-induced hepatocellular adenomas (HCA; n=3), and hepatocellular carcinomas (HCC; n=3), compared with age-matched normal livers (n=5). To investigate functional networks and gene ontology, two clusters were analyzed by Ingenuity Pathway Analysis. Clustering analysis of global genes demonstrated gene profiles of HCA and HCC to greatly differ from those of age-matched normal liver. However, after treatment with MeIQx for 4 or 16 weeks, no major differences were apparent. Ingenuity Pathway Analysis suggested pathways related to the cell cycle and glutathione metabolism may be involved in MeIQx-induced hepatocarcinogenesis. Real-time PCR analysis confirmed elevation of cyclin B1, cell division cycle 2, glutathione peroxidase 2 and glutathione S-transferase A2 in tumors, but not in early stage livers. In conclusion, molecular signatures of MeIQx-induced tumors clearly vary from that of age-matched normal liver, but no such shift is evident at early stages of hepatocarcinogenesis.

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