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

作者：Yunfeng Bai, Hironori Edamatsu, Sakan Maeda, Hiromitsu Saito, Noboru Suzuki, Takaya Satoh, Tohru Kataoka · 发表于：Cancer Research · 年份：2004 · DOI：10.1158/0008-5472.can-04-3143 · 被引用次数：207 · 研究领域：Protein Kinase Regulation and GTPase Signaling、PI3K/AKT/mTOR signaling in cancer、Melanoma and MAPK Pathways

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