Ruolo della regolazione trascrizionale e post- trascrizionale della metionina adenosiltrasferasi nel Scuola dell'epatocancerogenesi

Aim: Mat1A and Mat2A genes encode the two methionine adenosyltransferase iso-enzymes which catalyze SAM biosynthesis. Low SAM, the product of MAT genes, content favors HCC development in rodents and humans. Overall DNA hypomethylation, associated with promoter hypermethylation and inactivation of tumor suppressor genes, occurs during liver carcinogenesis (HCC).These observations suggest the implication of epigenetic regulation of MAT isozymes expression in HCC development. We investigated the prognostic role ofMAT1A:MAT2A ratio, and the regulation ofMAT1AandMAT2Aexpression through the methylation status of promoter and mRNA stability during progression of hepatocarcinogenesis.Methods: We performed Mat1A and Mat2A Promoter Methylation, Quantitative Real-Time Reverse Trascription, Chromatin Immunoprecipitation assay, RNA protein interaction, Western Blot Analysis in rat and humans samples.Results: Our results show a marked decrease of Mat1A expression and MATI/III activity, and an increase in Mat2A expression and MATII activity in DN and HCC of F344 rats, and in samples human SLP and HCCP compared with normal liver, whereas low/no changes in DN and HCC of resistents BN rats and in human SLB and HCCB compared with normal liver.These results have been associated with CCGG methylation Mat1A of promoter, and CCGG hypomethylation of Mat2A promoter.A rise in AUF1 and HuR protein levels and of their interaction withMat1AandMat2AmRNAs, occurred in F344 rat and human HCC, respectively. AUF1/Mat1A and HuR/Mat2A interactions increased in BN HCC and in surrounding tissue, compared to F344 lesions.Conclusion: AUF1-Mat1A, Hur-Mat2A and promoter methylation ofMAT1AandMAT2Agenes are functionally controlled by cancer modifiers. Our data indicate, for the first time, a posttranscriptional regulation ofMAT1AandMAT2Aby AUF1 and HuR in HCC. We have demonstrated that a lowMAT1A:MAT2Aratio is a prognostic marker that contributes to determine a phenotype susceptible to HCC and patients survival.