Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor
Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor
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DOI：
10.1093/carcin/bgi220
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发表时间：
2006-02-01
期刊：
影响因子：
4.7
通讯作者：
Hansen, LA
中科院分区：
文献类型：
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作者：
El-Abaseri, TB;Putta, S;Hansen, LA
长期暴露于紫外线（UV）照射诱导皮肤癌，部分是通过表观遗传机制，导致细胞增殖的失调。紫外线照射也迅速激活表皮生长因子受体（EGFR）。由于EGFR活化在包括皮肤角质形成细胞在内的许多细胞类型中具有强烈的促有丝分裂作用，因此我们假设UV诱导的皮肤增殖是由EGFR活化引起的。EGFR激活在皮肤对UV的反应中的作用是使用Egfr-null和Egfr-野生型皮肤移植到无胸腺裸鼠宿主上来确定的，因为Egfr-null小鼠在出生后仅存活几天。EGFR在暴露于UV后在小鼠表皮中迅速活化，如通过EGFR在酪氨酸残基992、1045、1068和1173上的磷酸化检测的。在UV后48和72小时之间，在Egfr野生型皮肤中UV诱导表皮增生。然而，没有表皮增生发生在表皮生长因子受体无效的皮肤。两种基因型皮肤移植物的基线细胞增殖相似。然而，紫外线照射增加细胞增殖，Ki 67免疫组化和增殖细胞核抗原免疫印迹法测定，最大在48小时的水平超过3倍以上的野生型相比，表皮生长因子受体无效的皮肤。与紫外线照射后1-2天的野生型相比，通过末端脱氧核苷酸转移酶生物素-dUTP缺口末端标记（TUNEL）分析测量的细胞凋亡在紫外线暴露的Egfr缺失皮肤中也有所增加。紫外线照射后细胞内稳态的这些变化伴随着细胞周期蛋白D在野生型皮肤中的表达增加，而不是Egfr-null皮肤，与野生型相比，Egfr-null皮肤中p53和细胞周期蛋白依赖性激酶（CDK）抑制剂p21（waf 1）的表达增加。总的来说，这些结果表明，紫外线诱导的EGFR活化增强角质形成细胞增殖和抑制凋亡，导致表皮增生，与增加G（1）细胞周期蛋白表达和抑制CDK抑制剂表达。
Chronic exposure to ultraviolet (UV) irradiation induces skin cancer, in part, through epigenetic mechanisms that result in the deregulation of cell proliferation. UV irradiation also rapidly activates the epidermal growth factor receptor (EGFR). Since EGFR activation is strongly mitogenic in many cell types including keratinocytes of the skin, we hypothesized that UV-induced cutaneous proliferation results from EGFR activation. The role of EGFR activation in the response of the skin to UV was determined using Egfr-null and Egfr-wild-type skin grafted onto athymic nude mouse hosts, because Egfr-null mice survive only a few days after birth. EGFR was rapidly activated in mouse epidermis following exposure to UV, as detected by the phosphorylation of EGFR on tyrosine residues 992, 1045, 1068 and 1173. UV induced epidermal hyperplasia in Egfr-wild-type skin between 48 and 72 h post-UV. However, no epidermal hyperplasia occurred in Egfr-null skin. Baseline cell proliferation was similar in skin grafts of both genotypes. However, UV exposure increased cell proliferation, as measured by Ki67 immunohistochemistry and proliferating cell nuclear antigen immunoblotting, maximally at 48 h to a level more than three times higher in wild-type compared with Egfr-null skin. Apoptotic cell death, as measured by terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) analysis, was also increased in UV-exposed Egfr-null skin when compared with wild-type 1-2 days post-UV. These changes in cellular homeostasis after UV were accompanied by increased cyclin D expression in wild-type but not Egfr-null skin and increased expression of p53 and the cyclin-dependent kinase (CDK) inhibitor p21(waf1) in Egfr-null skin when compared with wild-type. Collectively, these results demonstrate that the UV-induced activation of EGFR augments keratinocyte proliferation and suppresses apoptosis, leading to epidermal hyperplasia, associated with increased G(1) cyclin expression and suppression of CDK inhibitor expression.