Abstract

Background and Aims: Genomic instability (GI) is involved in rodent and human hepatocellular carcinoma (HCC) pathogenesis. DNA hypomethylation may drive malignant transformation by generating GI, but whether DNA hypomethylation is a prerequisite for HCC development remains unclear. We investigated the correlation between GI and DNA methylation, and influence of methionine metabolism deregulation on these parameters in c-Myc and c-Myc/Tgf-a transgenic mouse models of HCC. Methods: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver content was assessed by HPLC, activity of methionine adenosyltransferases by enzymatic assay, levels of methionine metabolism regulators by RT-PCR, GI by RAPD, and global DNA methylation by [³ H]dCTP incorporation into DNA. Results: SAMiSAH ratio and liver-specific methionine adenosyltransferase levels progressively decreased in dysplastic and neoplastic liver of c-Myc transgenic mice, leading to global DNA hypomethylation and GI, but not in c-Myc/Tgf-cc lesions, where highest GI correlated with proliferative activity. Upregulation of genes involved in polyamine synthesis, methionine salvage, and downregulation of polyamine negative regulator OAZl, was highest in c-MyciTgf-a HCCs, indicating SAM requirement for polyamine-induced growth in aggressive c-MyciTgf-a HCCs. Conclusions: Our results indicate that aggressive HCC may develop in the absence of DNA hypomethylation. Genome-wide hypomethylation may favor development of slow growing HCC with relatively low GI and polyamine synthesis.

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