Xeroderma pigmentosum group A gene action as a protection factor against 4-nitroquinoline 1-oxide-induced tongue carcinogenesis.
To test the hypothesis that nucleotide excision repair (NER) plays a protective role in chemical carcinogenesis in internal organs, xeroderma pigmentosum group A gene-deficient (XPA(-/-)) mice, heterozygous (XPA(+/-)) and wild-type (XPA(+/+)) mice were orally administered 0.001% 4-nitroquinoline 1-oxide (4NQO) in their drinking water and compared. After 50 weeks of 4NQO exposure, tongue squamous cell carcinomas (SCCs) occurred in XPA(-/-) mice only, no tumors being observed in XPA(+/-) and XPA(+/+) animals. Of the XPA(-/-) mice 86% had tumors and 100% demonstrated multiple foci of dysplastic epithelium in the tongue. Accumulation of p53 protein was immunohistochemically detected in 56% of the SCCs. Mutational analysis of the p53 gene (exons 4-10) in carcinoma DNA revealed missense mutations in exons 5 and 9 in four of 20 samples. Our results clearly demonstrate that the NER gene XPA acts as a defensive factor against 4NQO-induced tongue carcinogenesis in vivo.
Ide
F
F
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Oda
H
H
Nakatsuru
Y
Y
Kusama
K
K
Sakashita
H
H
Tanaka
K
K
Ishikawa
T
T
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000517:prevention & control; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D020125:Mutation, Missense; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014059:Tongue / Q000187:drug effects / Q000473:pathology; D014062:Tongue Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051760:Xeroderma Pigmentosum Group A Protein
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015112:4-Nitroquinoline-1-oxide