El-Abaseri Taghrid B, Fuhrman Jill, Trempus Carol, Shendrik Igor, Tennant Raymond W, Hansen Laura A
Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska 68178, USA.
Cancer Res. 2005 May 1;65(9):3958-65. doi: 10.1158/0008-5472.CAN-04-2204.
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 approximately 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.
表皮生长因子受体（EGFR）在紫外线照射后的皮肤细胞中被激活，紫外线照射是非黑色素瘤皮肤癌的主要病因。EGFR抑制剂AG1478可防止紫外线诱导的EGFR激活以及皮肤中通过c-Jun氨基末端激酶、细胞外信号调节激酶、p38激酶和磷脂酰肌醇3激酶的下游信号通路激活。在对皮肤致癌作用敏感性增强的基因启动的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。在紫外线暴露前局部治疗或腹腔注射AG1478可阻断皮肤中紫外线诱导的EGFR激活，并减少Tg.AC小鼠的皮肤肿瘤发生。在几次紫外线暴露前每次进行AG1478治疗，可使产生的乳头状瘤数量和这些肿瘤的生长分别减少约50%和80%。抑制EGFR可抑制增殖、增加凋亡细胞死亡，并延迟紫外线照射后表皮增生的发生。Egfr基因敲除同样可延迟对紫外线暴露的表皮增生反应。因此，紫外线诱导的EGFR激活通过抑制细胞死亡、增强细胞增殖和加速对紫外线的表皮增生来促进皮肤肿瘤发生。这些结果表明，EGFR可能是化学预防紫外线诱导的皮肤癌的合适靶点。
