Vorce R L, Goodman J I
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Mol Toxicol. 1989 Apr-Jun;2(2):99-116.
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.
雄性杂交B6C3F1小鼠自发性肝癌发生率为30%，该品系的雄性和雌性小鼠对化学诱导的肝肿瘤均敏感。Ha-ras、Ki-ras和myc癌基因与多种实体瘤有关。具体而言，已有报道称Ha-ras以及较少见的Ki-ras在B6C3F1小鼠肝肿瘤中被激活，且此类激活的癌基因通常含有特定的点突变。鉴于有迹象表明某些癌基因的转化能力与基因产物水平直接相关，我们推测在B6C3F1小鼠肝肿瘤中，Ha-ras、Ki-ras和myc的转录调控受到损害。基因表达与低甲基化之间已建立正相关。因此，在自发性肝肿瘤以及由两种不同的肝癌致癌物（苯巴比妥和氯仿）诱导的肿瘤中检测了这些基因的甲基化状态。在所检测的所有肿瘤中均发现Ha-ras低甲基化，而Ki-ras有时低甲基化；这种低甲基化可能在致癌作用的促进阶段发挥作用。myc的甲基化状态未改变，尽管该基因在肿瘤中似乎有扩增。这些结果表明，在B6C3F1小鼠肝肿瘤中激活这些癌基因的机制的一个组成部分涉及通过ras癌基因的低甲基化以及可能的myc扩增而丧失对表达的严格控制。这些结果支持这样的论断，即由不同类致癌物诱导或自发产生的肿瘤在肿瘤发生过程中共享癌基因激活的共同生化途径。
