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Xeroderma pigmentosum group A gene action as a protection factor against 4-nitroquinoline 1-oxide-induced tongue
1Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Abstract:
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.
Insights
Nucleotide excision repair (NER) deficiency accelerates chemical carcinogenesis. Mice lacking the XPA gene developed tongue tumors after 4-nitroquinoline 1-oxide exposure, unlike normal mice, highlighting NER
Area of Science:
- Molecular Biology
- Genetics
- Carcinogenesis Research
Background:
- DNA repair mechanisms are crucial for preventing mutations that can lead to cancer.
- Nucleotide excision repair (NER) is a major DNA repair pathway involved in removing bulky, helix-distorting DNA lesions.
- Xeroderma pigmentosum group A (XPA) is a key component of the NER pathway, essential for recognizing DNA damage.
Purpose of the Study:
- To investigate the role of the NER pathway, specifically the XPA gene, in protecting against chemical-induced carcinogenesis in internal organs.
- To determine if XPA deficiency influences the development of tumors following exposure to 4-nitroquinoline 1-oxide (4NQO).
Main Methods:
- Xeroderma pigmentosum group A gene-deficient (XPA(-/-)), heterozygous (XPA(+/-)), and wild-type (XPA(+/+)) mice were orally administered 4-nitroquinoline 1-oxide (4NQO).
- Mice were monitored for tumor development over 50 weeks.
- Tumor incidence, histopathology, p53 protein accumulation, and p53 gene mutations were analyzed in affected tissues.
Main Results:
- All XPA(-/-) mice developed tongue squamous cell carcinomas (SCCs) after 50 weeks of 4NQO exposure (86% incidence with tumors).
- No tumors were observed in XPA(+/-) or XPA(+/+) mice.
- XPA(-/-) mice showed widespread epithelial dysplasia, p53 accumulation in 56% of SCCs, and missense mutations in the p53 gene in four of 20 samples.
Conclusions:
- The NER gene XPA functions as a critical defensive factor against 4NQO-induced tongue carcinogenesis.
- XPA deficiency significantly enhances susceptibility to chemical carcinogenesis in vivo.
- These findings underscore the importance of NER in preventing cancer development.