Pro-inflammatory roles of ultraviolet radiation in cutaneous photocarcinogenesis

Previously, it was thought that ultraviolet radiation (UV) carcinogenesis was caused by accumulation of mutations related to cancer, including oncogenes and tumor suppressor genes. These genetic changes found in skin cancers are considered to be induced by UV, based on the findings that "UV-signature mutations" are predominant. However, recent findings revealed that UV carcinogenesis includes a more complicated process, and the importance of inflammation is emphasized. It is evident that DNA lesions cause inflammation. We showed that Ogg1 knockout mice, which fail to repair 8-OxoG, a representative oxidative DNA lesion, manifest a much higher frequency of UV-induced skin cancers without increasing p53 mutations. Gene expression analysis in this system revealed that 8-oxoG upregulates inflammatory pathway genes. Furthermore, a mice model of xeroderma pigmentosum, a DNA repair disorder, where patients manifest severe sunburn and high frequency of skin cancers, was demonstrated to express an extremely high level of CXCL1, an inflammatory chemokine. Inhibiting CXCL1 decreased the development of UV-induced skin cancers without repairing dipyrimidine photoproducts. Additionally, some anti-inflammatory medicines suppress the development of UV-induced skin cancers. The enhancement of photosensitive medications, including voriconazole and hydrochlorothiazide on UV carcinogenesis, has been indicated both epidemiologically and experimentally.