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Crucial Role of Phospholipase C in Chemical Carcinogen-Induced Skin Tumor Development

¹ Division of Molecular Biology, Department of Molecular and Cellular Biology and ² Division of Molecular Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Kobe, Japan; and ³ Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Mie, Japan

Mutational activation of the ras proto-oncogenes is frequently found in skin cancers. However, the nature of downstream signaling pathways from Ras involved in skin carcinogenesis remains poorly understood. Recently, we and others identified phospholipase C (PLC) as an effector of Ras. Here we have examined the role of PLC in de novo skin chemical carcinogenesis by using mice whose PLC is genetically inactivated. PLC^–/– mice exhibit delayed onset and markedly reduced incidence of skin squamous tumors induced by initiation with 7,12-dimethylbenz(a)anthracene followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, the papillomas formed in PLC^–/– mice fail to undergo malignant progression into carcinomas, in contrast to a malignant conversion rate of approximately 20% observed with papillomas in PLC^+/+ mice. In all of the tumors analyzed, the Ha-ras gene is mutationally activated irrespective of the PLC background. The skin of PLC^–/– mice fails to exhibit basal layer cell proliferation and epidermal hyperplasia in response to TPA treatment. These results indicate a crucial role of PLC in ras oncogene-induced de novo carcinogenesis and downstream signaling from TPA, introducing PLC as a candidate molecular target for the development of anticancer drugs.

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