8-oxoguanine formation induced by chronic UVB exposure makes Ogg1 knockout mice susceptible to skin carcinogenesis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-07, Vol.65 (14), p.6006-6010
• Main Authors: KUNISADA, Makoto, SAKUMI, Kunihiko, TOMINAGA, Yohei, BUDIYANTO, Arief, UEDA, Masato, ICHIHASHI, Masamitsu, NAKABEPPU, Yusaku, NISHIGORI, Chikako
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cocarcinogenesis; DNA Damage; DNA Glycosylases - deficiency; DNA Glycosylases - genetics; Female; Genetic Predisposition to Disease; Guanine - analogs & derivatives; Guanine - biosynthesis; Immunohistochemistry; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Pharmacology. Drug treatments; Skin Neoplasms - etiology; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Tumors; Ultraviolet Rays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-0724

8-Oxoguanine is one of the oxidative DNA damages that can result in stable mutations. The Ogg1 gene encodes the repair enzyme 8-oxoguanine-DNA glycosylase, which removes the oxidized base from DNA. In this study, we investigated the role of 8-oxoguanine in skin carcinogenesis induced by UVB irradiation using Ogg1 knockout mice (C57Bl/6J background). We examined the effect of UVB irradiation on the formation of 8-oxoguanine in epidermal cells using immunostaining and found that the level of 8-oxoguanine in Ogg1 knockout mice 24 hours after UVB irradiation remained high compared with that in wild-type and heterozygous mice. To verify the effect of chronic UVB irradiation on 8-oxoguanine formations in epidermal cells, we irradiated wild-type, heterozygous, and Ogg1 knockout mice with UVB at a dose of 2.5 kJ/m2 thrice a week for 40 weeks. We found that the mean number of tumors in Ogg1 knockout mice was 3.71, which was significantly more than in wild-type and heterozygous mice, being 1.71 and 2.28, respectively. The rate of developing malignant tumors in Ogg1 knockout mice was also significantly higher (88.5%; squamous cell carcinomas, 73.1%; sarcomas, 15.4%) than in wild-type mice (50.0%; squamous cell carcinomas, 41.7%; sarcomas, 8.3%). Moreover, the age of onset of developing skin tumors in Ogg1 knockout mice was earlier than in the other types of mice. These results clearly indicate that oxidative DNA damage induced by sunlight plays an important role in the development of skin cancers.