Protein Kinase C Epsilon Signals Ultraviolet Light‐induced Cutaneous Damage and Development of Squamous Cell Carcinoma Possibly Through Induction of Specific Cytokines in a Paracrine Mechanism¶

Abstract

ABSTRACTProtein kinase C (PKC), a family of phospholipid‐dependent serine/threonine kinases, is not only the major intracellular receptor for the mouse skin tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) but also is activated by a variety of stress factors including ultraviolet radiation (UVR). PKCɛ is among six isoforms (α, δ, ɛ, η, μ and ζ) expressed in the mouse skin. To determine the in vivo functional specificity of PKCɛ in mouse skin carcinogenesis, we generated PKCɛ transgenic mouse (FVB/N) lines 224 and 215 that overexpress PKCɛ protein approximately 8‐ and 18‐fold, respectively, over endogenous levels in the basal epidermal cells and cells of the hair follicle. PKCɛ transgenic mice were observed to be highly sensitive to the development of papilloma‐independent metastatic squamous cell carcinoma (mSCC) elicited either by repeated exposure to UVR or by the 7,12‐Dimethylbenzanthracene–TPA tumor promotion protocol. The development of squamous cell carcinoma (SCC) appears to be linked to the PKCɛ‐mediated induction of cytokine tumor necrosis factor–α(TNFα). Immunohistochemical analysis for the expression of PKCɛ in the SCC of PKCɛ transgenic mice revealed that PKCɛ was not expressed in the tumor itself; however, the uninvolved tissue surrounding the SCC exhibited intense PKCɛ expression. Also, human SCC, similar to mouse SCC, did not express PKCɛ in the tumor, whereas the surrounding uninvolved epidermis revealed strong PKCɛ expression. These findings in both the PKCɛ mouse model and human SCC indicate that overexpression of PKCɛ in epidermis may lead to a microenvironment, which is suitable for enhancing the development of mSCC by a paracrine mechanism involving specific cytokines including TNFα.