Hypomethylation of ras oncogenes in chemically induced and spontaneous B6C3F1 mouse liver tumors.

Molecular toxicology Pub Date : 1989-04-01
R L Vorce, J I Goodman
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Abstract

The male hybrid B6C3F1 mouse exhibits a 30% spontaneous hepatoma incidence, and both males and females of this strain are sensitive to chemical induction of liver tumors. The Ha-ras, Ki-ras, and myc oncogenes have been implicated in a variety of solid tumors. Specifically, Ha- and, less frequently Ki-ras have been reported to be activated in B6C3F1 mouse liver tumors, and such activated oncogenes frequently contain a particular point mutation. In light of indications that the transforming capacity of some oncogenes is directly related to the level of the gene product, we hypothesized that transcriptional control of Ha-ras, Ki-ras, and myc is compromised in B6C3F1 mouse liver tumors. A positive correlation has been established between gene expression and hypomethylation. Therefore, the methylation states of these genes were examined in spontaneous liver tumors and in tumors induced by two diverse hepatocarcinogens: phenobarbital and chloroform. Ha-ras was found to be hypomethylated in all tumors examined, whereas Ki-ras was sometimes hypomethylated; such hypomethylation might play a role in the promotion stage of carcinogenesis. The methylation state of myc was unaltered, although this gene appeared to be amplified in tumors. These results suggest that a component of the mechanism by which these oncogenes are activated in B6C3F1 mouse liver tumors involves loss of stringent control of expression, via hypomethylation of the ras oncogenes and, possibly, amplification of myc. These results support the assertion that tumors induced by different classes of carcinogens or arising spontaneously share common biochemical pathways of oncogene activation during tumorigenesis.

ras癌基因在化学诱导和自发B6C3F1小鼠肝肿瘤中的低甲基化。
雄性杂交种B6C3F1小鼠自发性肝癌发生率为30%,且该品系雄性和雌性均对化学诱导肝肿瘤敏感。Ha-ras、Ki-ras和myc癌基因与多种实体瘤有关。具体来说,有报道称Ha-和较少出现的Ki-ras在B6C3F1小鼠肝肿瘤中被激活,这些被激活的癌基因通常包含一个特定的点突变。鉴于有迹象表明某些癌基因的转化能力与基因产物的水平直接相关,我们假设在B6C3F1小鼠肝肿瘤中Ha-ras、Ki-ras和myc的转录控制受到损害。基因表达与低甲基化之间存在正相关关系。因此,在自发性肝肿瘤和由两种不同的肝癌致癌物:苯巴比妥和氯仿诱导的肿瘤中,研究了这些基因的甲基化状态。在所有肿瘤中发现Ha-ras是低甲基化的,而Ki-ras有时是低甲基化的;这种低甲基化可能在癌变的促进阶段发挥作用。myc的甲基化状态没有改变,尽管该基因似乎在肿瘤中被扩增。这些结果表明,这些癌基因在B6C3F1小鼠肝肿瘤中被激活的机制的一个组成部分涉及通过ras癌基因的低甲基化和myc的可能扩增而失去严格的表达控制。这些结果支持由不同种类的致癌物诱导的肿瘤或自发产生的肿瘤在肿瘤发生过程中具有共同的癌基因激活生化途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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