Role of perturbation of methionine metabolism and global dna methylation in the generation of genomic instability in transgenic mouse models of liver cancer

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.