Ultraviolet light downregulates CD95 ligand and TRAIL receptor expression facilitating actinic keratosis and squamous cell carcinoma formation.
Long-term ultraviolet light exposure of human skin epidermis in Caucasians is associated with an increased risk for the development of melanoma and nonmelanoma skin cancers. Ultraviolet radiation not only induces DNA damage in epidermal cells, it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and apoptosis-preventing molecules. We demonstrate that, beside CD95 ligand, TRAIL and TRAIL receptors also function as important sensors in the human epidermis preserving skin integrity and preventing cell transformation. Ultraviolet irradiation extensively changes the expression pattern of some of these molecules, diminishing their sensor function. In particular, CD95 ligand and to a somewhat lesser extent TRAIL receptors are downregulated upon ultraviolet light exposure. CD95 ligand downregulation is not due to protein degradation as in situ hybridization experiments strongly support a transcriptional regulation. The downregulation of these molecules with sensor function increases the risk that aberrant cells are less efficiently eliminated. This concept is supported by the fact that the expression of these molecules is also low or absent in actinic keratosis, a precancerous state that has developed as the consequence of long-term ultraviolet exposure. Progression to invasive neoplasms is then accompanied by an upregulation of CD95 ligand and a downregulation of CD95 and of the TRAIL receptors. The high expression of CD95 ligand, TRAIL, and FLIP in squamous cell carcinoma may then contribute to the immune escape of the tumor, whereas the lack of expression of CD95 and TRAIL receptors prevents autolysis of the tumor.
Bachmann
F
F
Institute for Medical Microbiology, University of Basel, Basel, Switzerland.
Buechner
S A
SA
Wernli
M
M
Strebel
S
S
Erb
P
P
D000328:Adult; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation / Q000528:radiation effects; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D007642:Keratosis / Q000378:metabolism / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D010787:Photosensitivity Disorders / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D012867:Skin / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha