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-1α 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-1α and its target genes such as VEGF and the signaling pathway mediating such responses. We found that UV radiation induced HIF-1α 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-1α 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-1α and VEGF expression, in contrast, in egfr (+/+) MEF cells, UV radiation strongly induced HIF-1α and VEGF expression. EGFR kinase inhibitor, PD153035, inhibited UV-induced HIF-1α and VEGF protein expression in a dose-dependent manner. Further, we found that PI3K inhibitors, LY294002 and Wortmannin, inhibited HIF-1α and VEGF expression induced by UV radiation. In DEC1 (−/−) HaCat cells, UV radiation did not induce HIF-1α and VEGF expression, in contrast, in DEC1 (+/+) HaCat cells, UV radiation strongly enhanced HIF-1α and VEGF protein expression. We conclude that UV radiation induces HIF-1α and VEGF expression via the EGFR/PI3K/DEC1 signaling pathway.

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