title: UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway.
abstract: 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.
authors.affiliation: Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, P.R. China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Bi
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000077191:Wortmannin; C403671:DELEC1 protein, human; C497442:HIF1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline