Pascale R M, Simile M M, Feo F
Istituto di Patologia Generale dell' Universita di Sassari, Italy.
Anticancer Res. 1993 Sep-Oct;13(5A):1341-56.
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.
致癌作用是一个复杂的过程，其特征是各种癌基因的累积激活和抑癌基因的失活。表观遗传机制也参与其中。在大多数自发或致癌物诱导的肝肿瘤中，在易感小鼠中，以及在癌前病变中较少发生ras家族基因的突变激活。这表明这些变化在小鼠肝癌发生中具有致病作用。在大鼠肝癌发生过程中，各种生长相关基因在癌前组织中过表达，但原癌基因的突变激活，尤其是ras家族基因的突变激活，似乎是一个晚期且罕见的事件，而c-myc扩增在啮齿动物和人类致癌过程中是一个晚期但常见的事件。然而，在大鼠肝脏相对早期的癌前病变中发现了抑癌基因p53的突变，并且在人类肝细胞癌中可能经常见到。这种突变参与肝癌发生起始阶段的可能性是一个有吸引力的假设，需要进一步评估。DNA低甲基化参与致癌作用，但其潜在机制仍不清楚。生长相关基因的低甲基化与其过表达相关，这可能有利于癌前肝组织的过度生长。在喂食甲基缺乏饮食的大鼠肝脏中，以及在喂食充足饮食的启动/促进大鼠中发生的癌前肝组织中，S-腺苷甲硫氨酸/S-腺苷同型半胱氨酸（SAM/SAH）比值降低，甲基缺乏饮食是一种致癌处理。促脂化合物的肿瘤化学预防作用证实了低SAM/SAH比值在致癌作用中的作用。用外源性SAM治疗可预防大鼠肝脏癌前和肿瘤病变的发展。这与SAM/SAH比值的恢复、DNA甲基化以及生长相关基因表达的抑制有关。5-氮杂胞苷（一种低甲基化剂）消除了SAM对癌前细胞生长的作用，表明DNA甲基化的参与。在SAM处理的大鼠中，甲基化和生长相关基因表达的抑制与生长抑制有关的可能性很有吸引力，应该进一步评估。通过DNA甲基化或其他表观遗传机制影响基因表达来调节大鼠肝癌发生可能是预防这些肿瘤的一种新的化学预防方法。
