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Disruption of Protein Kinase C Results in Impairment of Wound Healing and Enhancement of Tumor Formation in Mouse Skin Carcinogenesis¹

Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan [K. C., T. Ha., T. Hi.]; Department of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [C. K.]; Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan [K. Nakam.]; RIKEN Center for Developmental Biology, Hyogo 650-0047, Japan [K. Nakao]; Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan [A. A.]; National Institute of Basic Biology, Aichi 444-8585, Japan [M. K.]; and Gifu University, Gifu 501-1193, Japan [T. K.]

We have generated a mouse strain lacking protein kinase C (PKC) to evaluate its significance in epithelial organization and tumor formation. The PKC-deficient mice exhibited increased susceptibility to tumor formation in two-stage skin carcinogenesis by single application of 7,12-dimethylbenz(a)anthracene (DMBA) for tumor initiation and repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion. The tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKC suppresses tumor promotion. Epidermal hyperplasia induced by topical TPA treatment was prolonged in the mutant mice. The enhanced tumor formation may be closely associated with the prolonged hyperplasia induced by topical TPA treatment. In the mutant mice, after inflicting injury by punch biopsy, wound healing on the dorsal skin, particularly reepithelialization, was significantly delayed and impaired in structure. Impairment of epithelial regeneration in wound healing indicates a possibility that PKC plays a role in maintenance of epithelial architecture. Homeostasis in epithelial tissues mediated by PKC is important for tumor formation in vivo. We propose that PKC is involved in tumor formation modulated by regulation of proliferation and remodeling of epithelial cells in vivo.

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