Li Yanhua, Bi Zhigang, Yan Bingfang, Wan Yinsheng
Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, P.R. China.
Int J Mol Med. 2006 Oct;18(4):713-9.
EGFR is involved in the UV signal transduction pathway leading to skin cancer. UV radiation, mediated by EGFR, induces activation of PI3 kinase and AKT with a result of activation of a number of transcription factors. Transcription factor HIF-1alpha correlates with tumorigenicity and angiogenesis. Transcription factors DEC1 and DEC2 also play pivotal roles in multiple signaling pathways impacting various biological processes including development, cell differentiation, cell death, and oncogenesis. We investigated whether UV radiation and associated hypoxia induce expression of HIF-1alpha and its target genes such as VEGF and the signaling pathway mediating such responses. We found that UV radiation induced HIF-1alpha and VEGF protein expression in a dose- and time-dependent manner in cultured human keratinocytes. UV radiation also induced VEGF mRNA expression in a dose-dependent manner with maximum effect at 4 h post treatment, but did not affect HIF-1alpha mRNA expression. We also observed that UV radiation induced activation of EGFR in a time- and dose-dependent manner which was inhibited by EGFR inhibitor PD153035. In egfr (-/-) MEF cells, UV radiation did not induce HIF-1alpha and VEGF expression, in contrast, in egfr (+/+) MEF cells, UV radiation strongly induced HIF-1alpha and VEGF expression. EGFR kinase inhibitor, PD153035, inhibited UV-induced HIF-1alpha and VEGF protein expression in a dose-dependent manner. Further, we found that PI3K inhibitors, LY294002 and Wortmannin, inhibited HIF-1alpha and VEGF expression induced by UV radiation. In DEC1 (-/-) HaCat cells, UV radiation did not induce HIF-1alpha and VEGF expression, in contrast, in DEC1 (+/+) HaCat cells, UV radiation strongly enhanced HIF-1alpha and VEGF protein expression. We conclude that UV radiation induces HIF-1alpha and VEGF expression via the EGFR/PI3K/DEC1 signaling pathway.
表皮生长因子受体（EGFR）参与导致皮肤癌的紫外线信号转导通路。由EGFR介导的紫外线辐射诱导磷脂酰肌醇-3激酶（PI3激酶）和蛋白激酶B（AKT）激活，结果是激活许多转录因子。转录因子低氧诱导因子-1α（HIF-1α）与肿瘤发生和血管生成相关。转录因子DEC1和DEC2在影响包括发育、细胞分化、细胞死亡和肿瘤发生等各种生物学过程的多个信号通路中也起着关键作用。我们研究了紫外线辐射和相关的缺氧是否诱导HIF-1α及其靶基因如血管内皮生长因子（VEGF）的表达以及介导这种反应的信号通路。我们发现紫外线辐射在培养的人角质形成细胞中以剂量和时间依赖性方式诱导HIF-1α和VEGF蛋白表达。紫外线辐射也以剂量依赖性方式诱导VEGF信使核糖核酸（mRNA）表达，在处理后4小时达到最大效应，但不影响HIF-1α mRNA表达。我们还观察到紫外线辐射以时间和剂量依赖性方式诱导EGFR激活，这被EGFR抑制剂PD153035抑制。在表皮生长因子受体基因敲除（egfr (-/-)）的小鼠胚胎成纤维细胞（MEF）中，紫外线辐射不诱导HIF-1α和VEGF表达，相反，在表皮生长因子受体基因正常（egfr (+/+)）的MEF细胞中，紫外线辐射强烈诱导HIF-1α和VEGF表达。EGFR激酶抑制剂PD153035以剂量依赖性方式抑制紫外线诱导的HIF-1α和VEGF蛋白表达。此外，我们发现PI3激酶抑制剂LY294002和渥曼青霉素抑制紫外线辐射诱导HIF-1α和VEGF表达。在DEC1基因敲除（DEC1 (-/-)）的永生化人角质形成细胞（HaCat）中，紫外线辐射不诱导HIF-1α和VEGF表达，相反，在DEC1基因正常（DEC1 (+/+)）的HaCat细胞中，紫外线辐射强烈增强HIF-1α和VEGF蛋白表达。我们得出结论，紫外线辐射通过EGFR/PI3K/DEC1信号通路诱导HIF-1α和VEGF表达。
