title: Genomic abnormalities in hepatocarcinogenesis. Implications for a chemopreventive strategy.
abstract: Carcinogenesis is a complex process characterized by the cumulative activation of various oncogenes and the inactivation of suppressor genes. Epigenetic mechanisms are also involved. Mutational activation of ras family genes occurs in most spontaneous or carcinogen-induced liver tumors, in susceptible mice, and less frequently in preneoplastic lesions. This suggests a pathogenetic role of these changes in hepatic carcinogenesis, in the mouse. Overexpression of various growth-related genes occurs in preneoplastic tissue during rat liver carcinogenesis, but mutational activation of protooncogenes, notably of ras family genes, seems to be a late and rare event, while c-myc amplification is a late but frequent event in both rodent and human carcinogenesis. However, mutation of the suppressor p53 gene has been found in relatively early preneoplastic lesions in rat liver, and it may be frequently seen in human hepatocellular carcinomas. The possibility that this mutation is involved in the initiation stage of liver carcinogenesis is an attractive hypothesis which needs further evaluation. DNA hypomethylation is involved in carcinogenesis, but the mechanisms underlying this effect are still elusive. Hypomethylation of growth-related genes is associated with their overexpression and this could favor overgrowth of preneoplastic liver tissue. Decrease in S-adenosyl methionine/S-adenosylhomocysteine (SAM/SAH) ratio occurs in the liver of rats fed a methyl deficient diet, which is a carcinogenic treatment, and in preneoplastic liver tissue, developing in initiated/promoted rats fed an adequate diet. The role of low SAM/SAH ratio in carcinogenesis is substantiated by the tumor chemopreventive effect of lipotropic compounds. Treatment with exogenous SAM prevents the development of preneoplastic and neoplastic lesions in rat liver. This is associated with recovery of SAM/SAH ratio, DNA methylation and inhibition of growth-related gene expression. SAM effect on prenoplastic cell growth is abolished by 5-azacytidine, a hypomethylating agent, indicating the involvement of DNA methylation. The possibility that in SAM-treated rats, methylation and inhibition of the expression of growth-related genes is implicated in growth restraint is attractive and should be further evaluated. Modulation of rat liver carcinogenesis by influencing gene expression through DNA methylation or other epigenetic mechanisms could be a new approach to chemoprevention of these tumors.
authors.affiliation: Istituto di Patologia Generale dell' Universita di Sassari, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Pascale
authors.forename: M M
authors.initials: MM
authors.lastname: Simile
authors.forename: F
authors.initials: F
authors.lastname: Feo
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000517:prevention & control; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000517:prevention & control; D004273:DNA, Neoplasm / Q000378:metabolism*; D003839:Deoxyadenosines / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000517:prevention & control; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D017354:Point Mutation / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics* / Q000517:prevention & control; D051381:Rats; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013872:Thionucleosides / Q000037:antagonists & inhibitors*
chemical_list: D004273:DNA, Neoplasm; D003839:Deoxyadenosines; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D012436:S-Adenosylmethionine