Carcinogenesis, Vol. 22, No. 4, 567-572,
April 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
Xeroderma pigmentosum group A gene action as a protection factor against 4-nitroquinoline 1-oxide-induced tongue carcinogenesis
1 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033,
2 Department of Oral Pathology and
3 Second Department of Oral and Maxillofacial Surgery, Meikai University School of Dentistry, Saitama 350-0283,
4 Division of Cellular Genetics, Institute for Molecular and Cellular Biology, Osaka University, Osaka 565-0871 and
5 National Institution for Academic Degrees, Faculty of University Evaluation and Research, 2-1-1 Hitotsubashi, Chiyoda-ku, Tokyo 101-0003, Japan
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.
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