Expression of n-MYC, NAMPT and SIRT1 in Basal Cell Carcinomas and their Cells of Origin
Lydia Brandl, Daniela Hartmann, Thomas Kirchner, Antje Menssen
Deregulated Hedgehog signalling is a driver of basal cell carcinomas. One effector of the Hedgehog pathway is n-MYC. c/n-MYC proteins, NAMPT and DBC1 are linked to SIRT1 in a positive feedback loop that may contribute to tumorigenesis of basal cell carcinoma. In 5 basal cell carcinoma types immunohistochemistry revealed n-MYC, NAMPT and SIRT1 expression. DBC1 was homogenously expressed in all epithelial cells. NAMPT, SIRT1 and c-MYC were expressed in the stratum basale of human and murine skin. In hair follicles NAMPT and SIRT1 were expressed together with c-MYC and n-MYC, except for the matrix, where n-MYC was strongly positive, but c-MYC expression was absent. Therefore, a common pathway connecting n-MYC, NAMPT and SIRT1 may be active in basal cell carcinomas and in their cells of origin. This pathway may contribute to the development of basal cell carcinomas. Targeting factors in the feedback loop may offer novel therapeutic options.
Basal cell carcinoma is a skin tumour with locally aggressive growth. Analysing human basal cell carcinomas, and human and murine normal skin, including hair follicles, we show that the proteins of the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop may be active in both the skin stem cell areas, which are considered the cells of origin, and in basal cell carcinomas. Therefore, the positive feedback loop may play a crucial role in the development of basal cell carcinomas. Since NAMPT and SIRT are targetable enzymes, our results may open novel avenues for therapeutic interventions in basal cell carcinomas.