Resistance of CD1d-/- mice to ultraviolet-induced skin cancer is associated with increased apoptosis.
Inhibition of p53-induced epidermal apoptosis, generation of p53 mutations, and suppressor T cells are the critical events responsible for the induction and development of UV-induced skin cancers. Recently, we demonstrated that CD1d knockout mice were resistant to UV-induced immunosuppression, prompting us to further address the role of CD1d in regulating UV carcinogenesis. We, therefore, investigated the response of wild-type (WT) and CD1d-/- mice to UV carcinogenesis. We found that although 100% of WT mice developed skin tumors after 45 weeks of UV irradiation, only 60% of CD1d-/- mice developed skin tumors. Surprisingly, keratinocytes and fibroblasts from CD1d-/- mice were more sensitive to UV-induced apoptosis and persisted longer than cells derived from WT mice. In addition, epidermis and dermis taken from chronically UV-irradiated CD1d-/- mice harbored significantly fewer p53 mutations than WT mice. Our findings identify an unexpected and novel function for CD1d as a critical molecule regulating UV carcinogenesis, by inhibiting apoptosis to prevent elimination of potentially malignant keratinocytes and fibroblasts.
Matsumura
Yasuhiro
Y
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
Moodycliffe
Angus M
AM
Nghiem
Dat X
DX
Ullrich
Stephen E
SE
Ananthaswamy
Honnavara N
HN
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000502:physiology*; D055610:Antigens, CD1d; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D011836:Radiation Tolerance; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
D018949:Antigens, CD1; D055610:Antigens, CD1d; D016159:Tumor Suppressor Protein p53