Calvisi, Diego Francesco and Simile, Maria Maddalena and Ladu, Sara and Pellegrino, Rossella and De Murtas, Valentina and Tomasi, Maria Lauda and Virdis, Patrizia and De Miglio, Maria Rosaria and Pascale, Rosa Maria and Feo, Francesco (2007) Role of perturbation of methionine metabolism and global dna methylation in the generation of genomic instability in transgenic mouse models of liver cancer. Journal of Hepatology, Vol. 46 (Supplement 1), S137. ISSN 0168-8278. Article.
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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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