Chemoprevention of UV light-induced skin tumorigenesis by inhibition of the epidermal growth factor receptor
Chemoprevention of UV light-induced skin tumorigenesis by inhibition of the epidermal growth factor receptor
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DOI：
10.1158/0008-5472.can-04-2204
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Hansen, LA
中科院分区：
文献类型：
--
作者：
El-Abaseri, TB;Fuhrman, J;Hansen, LA
紫外线照射后，皮肤细胞中的表皮生长因子受体(EGFR)被激活，这是非黑色素瘤皮肤癌的主要原因。EGFR抑制剂AG1478通过c-jun NH2末端激酶、细胞外信号调节激酶、p38激酶和皮肤中的磷脂酰肌醇3-激酶来阻止紫外线诱导的EGFR及其下游信号通路的激活。在遗传启动的v-ras(Ha)转基因Tg.AC小鼠中，确定了紫外线诱导的EGFR激活对皮肤肿瘤发生的影响程度，这些转基因小鼠对皮肤癌的易感性增加。局部治疗或ip。紫外线照射前注射AG1478可阻断紫外线诱导的皮肤中EGFR的激活，并减少Tg.AC小鼠皮肤肿瘤的发生。AG1478在每次紫外线照射前进行治疗，可使乳头状瘤的数量和这些肿瘤的生长分别减少50%和80%。抑制EGFR可抑制细胞增殖，增加细胞凋亡性死亡，并延缓紫外线照射后表皮增生的发生。基因消融EGFR类似地延缓了皮肤对紫外线暴露的反应。因此，紫外线诱导的EGFR活化通过抑制细胞死亡、促进细胞增殖和加速皮肤对紫外线的反应而促进皮肤肿瘤的发生。这些结果表明，EGFR可能是紫外线诱导的皮肤癌的化学预防的合适靶点。
The epidermal growth factor receptor (EGFR) is activated in skin cells following UV irradiation, the primary cause of nonmelanoma skin cancer. The EGFR inhibitor AG1478 prevented the UV-induced activation of EGFR and of downstream signaling pathways through c-Jun NH2-terminal kinases, extracellular signal-regulated kinases, p38 kinase, and phosphatidylinositol 3-kinase in the skin. The extent to which the UV-induced activation of EGFR influences skin tumorigenesis was determined in genetically initiated v-ras(Ha) transgenic Tg.AC mice, which have enhanced susceptibility to skin carcinogenesis. Topical treatment or i.p. injection of AG1478 before UV exposure blocked the UV-induced activation of EGFR in the skin and decreased skin tumorigenesis in Tg.AC mice. AG1478 treatment before each of several UV exposures decreased the number of papillomas arising and the growth of these tumors by similar to 50% and 80%, respectively. Inhibition of EGFR suppressed proliferation, increased apoptotic cell death, and delayed the onset of epidermal hyperplasia following UV irradiation. Genetic ablation of Egfr similarly delayed epidermal hyperplasia in response to UV exposure. Thus, the UV-induced activation of EGFR promotes skin tumorigenesis by suppressing cell death, augmenting cell proliferation, and accelerating epidermal hyperplasia in response to UV. These results suggest that EGFR may be an appropriate target for the chemoprevention of UV-induced skin cancer.