Crucial role of phospholipase Cε in skin inflammation induced by tumor-promoting phorbol ester
Crucial role of phospholipase Cε in skin inflammation induced by tumor-promoting phorbol ester
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DOI：
10.1158/0008-5472.can-07-3245
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Kataoka, Tohru
中科院分区：
文献类型：
--
作者：
Ikuta, Shuzo;Edamatsu, Hironori;Kataoka, Tohru
在两阶段的皮肤化学致癌作用中，佛波醇酯12-O-十四酰基佛波醇-13-乙酸酯（TPA）作为携带激活的ras癌基因的起始细胞的克隆扩增所必需的启动子。虽然蛋白激酶C（PKC）同工酶是TPA的主要靶点，但它们在肿瘤促进中的作用仍存在争议。我们以前报道过，缺乏Ras/Rap效应磷脂酶C的小鼠（PLC β（-/-）小鼠）在两个阶段的皮肤癌发生中表现出显着的抗肿瘤形成。PLC β（-/-）小鼠也没有表现出TPA诱导的基底层细胞增殖和表皮增生，表明PLC β在肿瘤促进中的作用。在这里，我们表明，PLC的（-/-）小鼠表现出对TPA诱导的皮肤炎症的抵抗力，通过减少水肿，粒细胞浸润，和表达的促炎细胞因子，白细胞介素-1 α（IL-1 α）进行评估。另一方面，角质形成细胞或真皮成纤维细胞在培养中的增殖潜力保持不受PLC介导的背景影响，这表明PLC介导的肿瘤促进作用可能归因于炎症反应的增强。在真皮成纤维细胞原代培养中，TPA可诱导PLC β脂肪酶活性的活化，这导致IL-1 α表达的诱导。使用小干扰RNA介导的敲低的实验表明，这种激活是由Rap 1介导的，Rap 1由TPA响应性鸟嘌呤核苷酸交换因子RasGRP 3激活。此外，TPA诱导的Rap 1和PLC β的激活被PKC抑制剂GF 109203 X抑制，表明PKC在TPA到PLC β的信号传导中起关键作用。这些结果表明，TPA的两个目标，RasGRP 3和PKC，参与TPA诱导的炎症通过PLC的激活，导致肿瘤的促进。
in two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase C epsilon (PLC epsilon(-/-) mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLC epsilon(-/-) mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLC epsilon in tumor promotion. Here, we show that PLC epsilon(-/-) mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-lot (IL-1 alpha). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLC epsilon background, suggesting that the PLC epsilon's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLC epsilon lipase activity, which leads to the induction of IL-1 alpha expression. Experiments using small interfering RNA-mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLC epsilon is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLC epsilon. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLC epsilon activation, leading to tumor promotion.