Loss of Fas-ligand expression in mouse keratinocytes during UV carcinogenesis

Skin cells containing excessive ultraviolet (UV) radiation-induced DNA dama ge are eliminated by apoptosis that involves the p53 pathway and Fas/Fas-Li gand (Fas-L) interactions. To determine whether dysregulation of apoptosis plays a role in skin cancer development through disruption of Fas/Fas-L int eractions, hairless SKH-hr1 mice were exposed to chronic UV irradiation fro m Kodacel-filtered FS40 lamps for 30 weeks. Their skin was analyzed for the presence of sunburn cells (apoptotic keratinocytes) and. for Fas and Fas-L expression at various time points. A dramatic decrease in the numbers of m orphologically identified sunburn cells and TUNEL-positive cells was detect ed as early as 1 week after chronic UV exposure began. After 4 weeks of chr onic UV exposure, these cells were barely detectable. This defect in apopto sis was paralleled by an initial decrease in Fas-L expression during the fi rst week of chronic UV irradiation and a complete loss of expression after 4 weeks. Fas expression, however, increased during the course of chronic UV exposure.p53 mutations were detected in the UV-irradiated epidermis as ear ly as 1 week after irradiation began and continued to accumulate with furth er UV exposure. Mice exposed to chronic UV began to develop skin tumors aft er approximately 8 weeks, and all mice had multiple skin tumors by 24 weeks . Most of the tumors expressed Fas but not Fas-L. We conclude that chronic UV exposure may induce a loss of Fas-L expression and a gain in p53 mutatio ns, leading to dysregulation of apoptosis, expansion of mutated keratinocyt es,and initiation of skin cancer.