Crucial role of phospholipase CE in chemical carcinogen-induced skin tumor development
Crucial role of phospholipase CE in chemical carcinogen-induced skin tumor development
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DOI：
10.1158/0008-5472.can-04-3143
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Kataoka, T
中科院分区：
文献类型：
--
作者：
Bai, YF;Edamatsu, H;Kataoka, T
ras原癌基因的突变激活经常在皮肤癌中发现。然而，从Ras参与皮肤癌发生的下游信号通路的性质仍然知之甚少。最近，我们和其他人确定磷脂酶C（PLC）E作为Ras的效应子。在这里，我们已经研究了PLC在从头皮肤化学致癌作用的作用，通过使用小鼠的PLC基因失活。用7，12-二甲基苯并（a）蒽诱导PLC（-/-）小鼠皮肤鳞状细胞肿瘤，然后用12-O-十四烷酰佛波醇-13-乙酸酯（TPA）促进，结果显示，肿瘤的发病延迟，发病率明显降低。此外，在PLC（-/-）小鼠中形成的乳头状瘤不能经历恶性进展为癌，与在PLC（+/+）小鼠中观察到的乳头状瘤的约20%的恶性转化率相反。在所有分析的肿瘤中，Ha-ras基因突变激活，而与PLC背景无关。PLC（-/-）小鼠的皮肤对TPA治疗没有表现出基底层细胞增殖和表皮增生。这些结果表明PLC在ras癌基因诱导的从头致癌和TPA的下游信号传导中起着至关重要的作用，从而将PLC作为开发抗癌药物的候选分子靶点。
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) E 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.