F. Bai et al., KI-RAS MUTATION AND CELL-PROLIFERATION OF LUNG LESIONS INDUCED BY 1-NITROPYRENE IN A J MICE/, Molecular carcinogenesis, 22(4), 1998, pp. 258-264
In this study, lung lesions were found in male A/J mice 24 wk after in
traperitoneal injection of l-nitropyrene (1-NP). The lesions were clas
sified into three categories: alveolar/bronchiolar hyperplasia, adenom
a, and adenocarcinoma. The proliferation kinetics of cells in the lesi
ons were evaluated by assessing proliferating cell nuclear antigen (PC
NA) expression and silver-staining nucleolar organizer regions (AgNORs
). Furthermore, the role of the Ki-ras gene in tumorigenesis was studi
ed by detecting point mutations in Ki-ras codons 12, 13, and 61 by pol
ymerase chain reaction and sequence analysis. The PCNA-positive rates
(+/- standard deviations) in various samples were as follows: 0% for s
pecimens from six untreated animals and six uninvolved areas, 4.26 +/-
3.94% for 19 hyperplasias (hyperplasias vs normal lung tissue, P < 0.
01), 13.24 +/- 6.35% for 25 adenomas (adenomas vs hyperplasias, P < 0.
01), and 38.0 +/- 9.63% for four adenocarcinomas (adenocarcinomas vs a
denomas, P < 0.01). The corresponding mean AgNOR scores were as follow
s: 1.10 +/- 0.05 for the untreated animals, 1.32 +/- 0.09 for the unin
volved areas, 1.72 +/- 0.59 for the hyperplasias (hyperplasias vs norm
al lung tissue, P > 0.05), 2.74 +/- 0.70 for the adenomas (adenomas vs
hyperplasias, P < 0.01), and 5.22 +/- 0.62 for the adenocarcinomas (a
denocarcinomas vs adenomas, P < 0.01). Ki-ras gene mutations were iden
tified in three of four (75%) adenocarcinomas, six of 23 (26%) adenoma
s, and two of 17 (12%) hyperplasias. No mutations were found in normal
lung tissue. The most frequent Ki-ras mutation was an arginine (CCA)
AT --> GC transition at codon 61 in exon 2. The PCNA-positive rates an
d AgNOR scores of cases with Ki-ras mutations were higher than those w
ithout an identified mutation (P < 0.05). Ki-ras mutations at codon 61
(Arg) may therefore influence the growth or development of l-NP-induc
ed lung lesions in A/J mice. Mol. Carcinog. 22:258-264, 1998. (C) 1998
Wiley-Liss. Inc.