8-hydroxyguanosine and Skin-Neoplasms

Phototherapy with narrow-band UVB (NB-UVB), with a peak exclusively at 311 nm wavelength, has been found to be more effective in treating a variety of skin diseases than conventional broad-band UVB (BB-UVB). To assess the difference in carcinogenic activity between NB-UVB and BB-UVB, we investigated skin tumor formation by irradiating albino hairless, Ogg1 knockout mice and C57BL/6J wild counterparts with these two UV sources. We found that the ratio of malignant skin tumors induced by NB-UVB was significantly higher than that induced by BB-UVB. There was no significant difference in carcinogenicity of skin tumor induced by NB-UVB between Ogg1 knockout and wild-type mice. To investigate the possible cause of different carcinogenic activity by the different UV sources, we examined three types of DNA damage: cyclobutane pyrimidine dimer (CPD), (6-4) photoproduct, and 8-oxoguanine (8-oxoG) induced by each UV source. We found that CPD formation following a minimum erythema dose (MED) by NB-UVB was significantly higher than that following 1 MED by BB-UVB, whereas the formation of (6-4) photoproducts and 8-oxoG following BB-UVB was significantly higher than those following NB-UVB exposure. These results suggest that CPD formation is closely related to the higher carcinogenic characteristics of NB-UVB. JID JOURNAL CLUB ARTICLE: For questions, answers and open discussion about this article please go to http://network.nature.com/.

Topics: Animals; Cell Transformation, Neoplastic; Cyclobutanes; DNA Glycosylases; Epidermis; Guanosine; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Photochemistry; Pyrimidine Dimers; Skin Neoplasms; Ultraviolet Rays

We hypothesized that a substantial portion of the mutagenic alterations produced in the basal layer of human skin by sunlight are induced by wavelengths in the UVA range. Using laser capture microdissection we examined separately basal and suprabasal keratinocytes from human skin squamous cell carcinomas and premalignant solar keratosis for both UVA- and UVB-induced adduct formation and signature mutations. We found that UVA fingerprint mutations were detectable in human skin squamous cell carcinomas and solar keratosis, mostly in the basal germinative layer, which contrasted with a predominantly suprabasal localization of UVB fingerprint mutations in these lesions. The epidermal layer bias was confirmed by immunohistochemical analyses with a superficial localization of cyclobutane thymine dimers contrasting with the localization of 8-hydroxy-2'-deoxyguanine adducts to the basal epithelial layers. If unrepaired, these adducts may lead to fixed genomic mutations. The basal location of UVA-rather than UVB-induced DNA damage suggests that longer-wavelength UVR is an important carcinogen in the stem cell compartment of the skin. Given the traditional emphasis on UVB, these results may have profound implications for future public health initiatives for skin cancer prevention.

Topics: Carcinoma, Squamous Cell; Guanosine; Humans; Mutation; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays