Hypomethylation of ras oncogenes in chemically induced and spontaneous B6C3F1 mouse liver tumors.
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.
Vorce
R L
RL
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Goodman
J I
JI
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000662:veterinary; D002725:Chloroform; D004273:DNA, Neoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics / Q000662:veterinary*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D008297:Male; D008745:Methylation; D051379:Mice; D010634:Phenobarbital; D015183:Restriction Mapping; D012376:Rodent Diseases / Q000235:genetics*
D004273:DNA, Neoplasm; D002725:Chloroform; D010634:Phenobarbital