K-ras mutations in lung tumors from p53 mutant mice exposed to cigarette smoke.
In this study, we used p53 transgenic mice to investigate whether mice carrying this germline mutation would be susceptible to tobacco smoke-induced lung tumorigenesis. We subjected male transgenic mice and their wild-type littermates to whole-body exposure to environmental cigarette smoke (ECS) for up to 9.5 months. K-ras gene expression was significantly increased, 28 days after ECS exposure, in the apparently healthy lung of p53 mutant mice. An increase of lung tumor incidence and multiplicity was observed in p53 transgenic mice after exposure to ECS for either 5 months, followed by recovery in air for 4.5 months, or 9.5 continuative months of exposure. Conversely, no tumorigenic effect was observed in their wild-type littermates. Sequence analysis of the K-ras gene indicated that mutations had occurred at codon 12, 13 or codon 61 in tumors both from the air control group and tobacco smoke treatment groups. K-ras mutations were found in 100 %, 100 % and 77 % of tumors from animals exposed to air, ECS for 5 months, followed by recovery in air for 4.5 months, and ECS for 9.5 continuative months, respectively. The K-ras mutations were seemingly not related to the p53 genotype of the animals or to ECS exposure. The mutation spectrum was similar in tumors from the different groups. An apparently higher incidence of K-ras codon 12 mutations in the 9.5 months ECS group was not statistically significant. These findings provide evidence that mice carrying a mutant p53 transgene appear to be more sensitive to ECS-induced lung tumors than the corresponding wild-type littermates. K-ras mutations seem to be independent of the p53 status but the early overexpression of this oncogene is related to the p53 status in ECS-exposed mice. These results suggest that tobacco smoke enhances lung tumorigenesis primarily through promoting spontaneously occurring K-ras mutations.
Yao
Ruisheng
R
Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
Wang
Yian
Y
D'Agostini
Francesco
F
Izzotti
Alberto
A
Lubet
Ronald A
RA
You
Ming
M
De Flora
Silvio
S
D000818:Animals; D001483:Base Sequence; D004781:Environmental Exposure; D016158:Genes, p53; D011905:Genes, ras; D018095:Germ-Line Mutation; D015994:Incidence; D008175:Lung Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D012906:Smoke / Q000009:adverse effects*
D012906:Smoke