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[Cancer Research 64, 8808-8810, December 15, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

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

Yunfeng Bai1, Hironori Edamatsu1, Sakan Maeda2, Hiromitsu Saito3, Noboru Suzuki3, Takaya Satoh1 and Tohru Kataoka1

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) {epsilon} as an effector of Ras. Here we have examined the role of PLC{epsilon} in de novo skin chemical carcinogenesis by using mice whose PLC{epsilon} is genetically inactivated. PLC{epsilon}–/– 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{epsilon}–/– mice fail to undergo malignant progression into carcinomas, in contrast to a malignant conversion rate of approximately 20% observed with papillomas in PLC{epsilon}+/+ mice. In all of the tumors analyzed, the Ha-ras gene is mutationally activated irrespective of the PLC{epsilon} background. The skin of PLC{epsilon}–/– mice fails to exhibit basal layer cell proliferation and epidermal hyperplasia in response to TPA treatment. These results indicate a crucial role of PLC{epsilon} in ras oncogene-induced de novo carcinogenesis and downstream signaling from TPA, introducing PLC{epsilon} as a candidate molecular target for the development of anticancer drugs.




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