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

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-13acetate (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.