Ultraviolet Light Downregulates CD95 Ligand and Trail Receptor Expression Facilitating Actinic Keratosis and Squamous Cell Carcinoma Formation

Abstract

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.

Expression of CD95 (Fas) in sun‐exposed human skin and cutaneous carcinomas

“…The loss of CD95 expression in BCCs was previously reported, 20 and our results confirm that observation. On the basis of our observations in chronically sun-exposed skin, and the data obtained from controlled UV light exposure of human skin in volunteers, 19 we found that changes in Fas expression follow a hyperbolic pattern. With initial actinic damage, Fas expression is up-regulated and is associated with apoptosis of sun-exposed keratinocytes.…”

“…Chronic exposure to sunlight (as evidenced by the presence of solar elastosis), up-regulates Fas expression, which extends up to the granular layer, similar to the experimental data. 12,18,19 With further sun-induced skin damage resulting in AK, which represents the earliest morphologic stage in development of skin carcinoma, there was marked down-regulation, or total loss of CD95 expression. This down-regulation was retained in invasive SCC.…”

Effect of Antiretroviral Therapy on Apoptosis Markers and Morphology in Peripheral Lymph Nodes of HIV-Infected Individuals

“…Paraffin sections of the lymph node tissue were immunohistochemically stained for the following antigens: CD4 (Novocastra, clone 1F6, dilution 1:20), CD8 (Dako Cytomation Copenhagen Denmark, clone, C8/144B), CD21 (Cell Marque, clone 2G9), p24 (Dako, clone Kal-1,1:4), Bcl-2 (Dako, clone 124), IL-7Ra (Santa Cruz Biotechnologies, 1:100), c-Flip [22] (1:400), Fas (Novocastra, clone GM30; 1:20), FasL [22] (1:80), TRAIL (Santa Cruz Biotechnologies, K-18, 1:75), and active caspase 3 (R&D; 1:1,500). The sections were stained according to the manufacturers' instructions; horse radish peroxidase (HRP)-conjugate (Envision + system, Dako) and AEC substrate (Dako) were used except for the CD4 stains, in which the ABC-Elite-Complex (Vector laboratories Inc, Burlingame, CA, USA) and DAB substrate (Dako) were used.…”

“…For all other cellular (CD4, interfollicular CD8, CD21) and apoptosis-related antigens (Bcl-2, c-Flip, IL-7Ra, Fas, FasL, active caspase 3), the gray level intensity was determined by computerassisted image analysis using the Openlab program (Improvision, Coventry, UK) as described by Bachmann et al [22].…”

Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis

“…Cryosections were made and stained to detect Gli2, Bcl-2 or cFlip. To quantitate their expression, computer-assisted image analysis was performed (Bachmann et al, 2001). The values obtained from the transfected sections were compared with the untransfected (nil) sections, which were set to 100%.…”