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Crucial Role of Phospholipase C in Skin Inflammation Induced by Tumor-Promoting Phorbol Ester

Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan

Requests for reprints: Tohru Kataoka, Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5380; Fax: 81-78-382-5399; E-mail: kataoka{at}people.kobe-u.ac.jp.

In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase C (PLC^–/– mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLC^–/– mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLC in tumor promotion. Here, we show that PLC^–/– mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1 (IL-1). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLC background, suggesting that the PLC's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLC lipase activity, which leads to the induction of IL-1 expression. Experiments using small interfering RNA–mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLC is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLC. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLC activation, leading to tumor promotion. [Cancer Res 2008;68(1):64–72]

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