UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway.
UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway.
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DOI：
10.3892/ijmm.18.4.713
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发表时间：
2006-10
影响因子：
5.4
通讯作者：
Yanhua Li;Z. Bi;B. Yan;Y. Wan
中科院分区：
文献类型：
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作者：
Yanhua Li;Z. Bi;B. Yan;Y. Wan
EGFR 参与导致皮肤癌的紫外线信号转导途径。由 EGFR 介导的紫外线辐射诱导 PI3 激酶和 AKT 的激活，从而激活许多转录因子。转录因子 HIF-1α 与致瘤性和血管生成相关。转录因子 DEC1 和 DEC2 在影响各种生物过程（包括发育、细胞分化、细胞死亡和肿瘤发生）的多个信号通路中也发挥着关键作用。我们研究了紫外线辐射和相关的缺氧是否会诱导 HIF-1α 及其靶基因（例如 VEGF）的表达以及介导此类反应的信号通路。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。 UV 辐射还以剂量依赖性方式诱导 VEGF mRNA 表达，在治疗后 4 小时效果最大，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，而这种激活被 EGFR 抑制剂 PD153035 抑制。在egfr（-/-）MEF细胞中，紫外线辐射不诱导HIF-1α和VEGF表达，相反，在egfr（+/+）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 PI3K 抑制剂 LY294002 和 Wortmannin 抑制紫外线辐射诱导的 HIF-1α 和 VEGF 表达。在DEC1(-/-)HaCat细胞中，紫外线辐射不诱导HIF-1α和VEGF表达，相反，在DEC1(+/+)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。
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.