Coni P, Pang J, Pichiri-Coni G, Hsu S, Rao P M, Rajalakshmi S, Sarma D S
Department of Pathology, University of Toronto, Ontario, Canada.
Carcinogenesis. 1992 Mar;13(3):497-9. doi: 10.1093/carcin/13.3.497.
Our earlier studies had demonstrated that inhibition of DNA methylation following carcinogen treatment potentiated initiation of the carcinogenic process in the rat liver system. The hepatic nodules developed by initiation-promotion protocols showed a characteristic hypomethylation in the cell-cycle-related genes c-fos, c-myc and c-Ha-ras. In the present study we have found that the gene for beta-hydroxy-beta-methyl glutaryl coenzyme A reductase, a major rate-limiting enzyme in the biogenesis of mevalonate, is also hypomethylated at both CCGG and GCGC sites and expressed in hepatic nodules. This gene, however, did not exhibit hypomethylation in CCGG sequences in non-nodular surrounding liver, livers from rats subjected to two-thirds partial hepatectomy, or exposed to initiator alone (1,2-dimethylhydrazine given 18 h after partial hepatectomy) or to diets containing 1% orotic acid alone (promoting regimen). The activity of the enzyme and mevalonate formation are positively correlated with DNA synthesis and cell proliferation--two key components of the carcinogenic process. Taken together, the results suggest that hypomethylation of specific genes occurs in the carcinogenic process and this altered pattern of DNA methylation may play a role in the growth of the nodules.
我们早期的研究表明，致癌物处理后抑制DNA甲基化可增强大鼠肝脏系统致癌过程的启动。通过启动-促进方案形成的肝结节在细胞周期相关基因c-fos、c-myc和c-Ha-ras中表现出特征性的低甲基化。在本研究中，我们发现β-羟基-β-甲基戊二酰辅酶A还原酶基因（甲羟戊酸生物合成中的一种主要限速酶）在CCGG和GCGC位点均发生低甲基化，并在肝结节中表达。然而，该基因在非结节性周围肝脏、接受三分之二部分肝切除术的大鼠肝脏、仅暴露于启动剂（部分肝切除术后18小时给予1,2-二甲基肼）或仅暴露于含1%乳清酸的饮食（促进方案）的大鼠肝脏的CCGG序列中未表现出低甲基化。该酶的活性和甲羟戊酸的形成与DNA合成和细胞增殖呈正相关，而DNA合成和细胞增殖是致癌过程的两个关键组成部分。综上所述，结果表明特定基因的低甲基化发生在致癌过程中，这种DNA甲基化模式的改变可能在结节生长中起作用。
