Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Michael Girardi

Subject Area(s)

Cellular biology, Immunology, Oncology

Abstract

Epidermal dendritic cells, called Langerhans cells (LC), were recently shown to facilitate DMBA/TPA-induced chemical carcinogenesis. LC contribution to UV-induced carcinogenesis, however, remains to be elucidated. We used the Langerin-DTA transgenic mouse model that lacks LC to characterize early and late effects of DNA damage in epidermis following exposure to UVB light. We found that LC density in LC-intact mice remains unchanged at 1hr and 24hr post 100 J/m2 UVB, suggesting that LC are poised to affect the surrounding epidermal cells following acute low-dose UVB exposure. During this time interval, LC-deficient mice had significantly fewer γH2Ax-positive cells within the epidermis, indicative of decreased UV- induced DNA damage in the absence of LC. However, when the pathognomonic direct and indirect UV-induced DNA lesions were measured (cyclobutane pyrimidine dimers and 8- oxoguanine, respectively), we found no differences in the absence or presence of LC, suggesting that LC may contribute to acute UV-induced DNA damage by a different, unidentified mechanism. Since mutant p53, a tumor suppressor protein highly associated with squamous cell carcinoma, arises from unrepaired DNA damage, we measured islands of clonally expanded keratinocytes harboring mutant following chronic UVB exposure. LC-deficient mice had significantly fewer p53 islands and a two-fold decrease in the total area occupied by p53 islands after 9 weeks of UVB irradiation, thus LC also contribute to the survival and proliferation of transformed keratinocytes during chronic UVB exposure. Collectively, these results suggest that LC influence DNA damage and clonal expansion in the surrounding epidermal cells in both acute and chronic UVB exposure. It provides new insight into the previously unknown role of LC in photocarcinogenesis with the objective to develop novel preventive and therapeutic targets against skin cancer.

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