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Deficiency of Protein Kinase C in Mice Results in Impairment of Epidermal Hyperplasia and Enhancement of Tumor Formation in Two-Stage Skin Carcinogenesis

¹ Graduate School of Agricultural and Life Sciences, University of Tokyo; ² Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan; ³ RIKEN Center for Developmental Biology, Hyogo, Japan; and ⁴ National Institute of Basic Biology, Aichi, Japan

Requests for reprints: Kazuhiro Chida, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan. Phone: 81-3-5841-8152; Fax: 81-3-5841-8152; E-mail: acchida{at}mail.ecc.u-tokyo.ac.jp.

We generated a mouse strain lacking protein kinase C (PKC) and evaluated the significance of the enzyme in epithelial hyperplasia and tumor formation. 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. Tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKC suppresses tumor promotion. However, the severity of epidermal hyperplasia induced by topical TPA treatment was markedly reduced. In mutant mice, the number of 5-bromo-2'-deoxyuridine–labeled epidermal basal keratinocytes increased 16 to 24 hours after topical TPA treatment as in the case of wild-type mice, but significantly decreased at 36 and 48 hours. Furthermore, the regenerating epithelium induced by skin wound significantly decreased in thickness but was not structurally impaired. The enhanced tumor formation may not be associated with epidermal hyperplasia. The induction levels of epidermal growth factor (EGF) receptor ligands, tumor growth factor (TGF-), and heparin-binding EGF-like growth factor, in the skin of mutant mice by TPA treatment were significantly lower than those in the skin of wild-type mice. PKC may regulate the supply of these EGF receptor ligands in basal keratinocytes, resulting in a reduced epidermal hyperplasia severity in the mutant mice. We propose that PKC positively regulates epidermal hyperplasia but negatively regulates tumor formation in two-stage skin carcinogenesis.

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