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

Protein 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.

Transgenic Overexpression of RasGRP1 in Mouse Epidermis Results in Spontaneous Tumors of the Skin

“…G-CSF and the related cytokine granulocyte macrophage colony-stimulating factor can promote keratinocyte growth and angiogenesis, and they have been associated with tumor growth and progression in human skin cancer models (14,15). In mice, a transgenic model for overexpression of PKCq in the epidermis, which is susceptible to the formation of metastatic squamous cell carcinomas, is highly sensitive to induction of specific cytokines, among them G-CSF, in response to the tumor promoter TPA and UV radiation (16). A, mutations in codon 61 of the Ha-ras proto-oncogene were evaluated by a PCR approach, as described in Materials and Methods, using genomic DNA isolated from tumor samples from seven transgenic mice (L, DNA ladder; lanes 1-7, tumor samples).…”

Protein Kinase Cε, which Sensitizes Skin to Sun's UV Radiation–Induced Cutaneous Damage and Development of Squamous Cell Carcinomas, Associates with Stat3

“…PKCq is among the six PKC isoforms (a, y, q, D, A, and~) expressed both in human and mouse epidermis (7,8). PKCq levels in mouse epidermis correlate to the susceptibility of transgenic mice to SCC development by UVR (4,9). In addition, constitutive activation of Stat3 is observed in UVR-induced development of either human or mouse SCC (10,11).…”

“…We have reported that targeted overexpression of protein kinase Cq (PKCq) in basal epidermal cells of FVB/N mice sensitizes skin to the development of SCC by UVR (4)(5)(6)(7)(8)(9). PKC is a family of phospholipid-dependent serine/threonine kinases (8).…”

Protein Kinase Cε Interacts with Signal Transducers and Activators of Transcription 3 (Stat3), Phosphorylates Stat3Ser727, and Regulates Its Constitutive Activation in Prostate Cancer

“…PKCq is a transforming oncogene (26) and a predictive biomarker of various human cancers (27), including prostate cancer (5). We found PKCq is linked to the development of SCC elicited either by the 7,12-dimethylbenz(a)anthracene-TPA protocol (28)(29)(30) or by repeated UV radiation (UVR) exposures (31,32). PKCq is also overexpressed in human prostate cancer (33).…”