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Different Frequencies and Patterns of ß-Catenin Mutations in Hepatocellular Carcinomas Induced by N-Nitrosodiethylamine and a Choline-deficient L-Amino Acid-defined Diet in Rats¹

Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Nara 634-8521, Japan

To allow a study of ß-catenin mutations in hepatocellular carcinomas (HCCs) induced by exogenous and endogenous carcinogens, we induced tumors in male Fischer 344 rats with N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet. Administration of the former was followed by partial hepatectomy with colchicine to induce cell cycle disturbance and a selection pressure regimen (K. Ohashi et al., Cancer Res., 56: 3474–3479, 1996; M. Tsutsumi et al., Jpn. J. Cancer Res., 87: 5–9, 1996). HCCs were obtained after 42 weeks. With continuous choline-deficient L-amino acid-defined feeding, tumors were sampled after 75 weeks. Total RNA was extracted from individual lesions and mutations in the glycogen synthase kinase-3ß phosphorylation consensus motif of ß-catenin were investigated by reverse transcriptase-PCR-single-strand conformation polymorphism analysis followed by nucleotide sequencing. Changes were detected in 5 of 11 HCCs induced by the exogenous carcinogen. The observed shifts of C:GG:C or C:GA:T at codon 33 and G:CT:A transversions at codon 34 were associated with ß-catenin protein accumulation and confirmed by Western blot analysis. Only 2 of 15 HCCs induced in the endogenous carcinogenesis regimen demonstrated mutations, those being transitions of C:GT:A at codon 41 without amino acid alteration. These results suggest that different genetic pathways underlie exogenous and endogenous liver carcinogenesis in rats.

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