期刊
HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
卷 37, 期 8, 页码 1150-1162出版社
WILEY
DOI: 10.1002/hed.23733
关键词
head and neck squamous cell carcinoma; epidermal growth factor; hypoxia inducible factor; BNIP3; gefitinib
资金
- Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria [FIS PI11/929]
- Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0015]
- Instituto de Salud Carlos III (ISCIII)
- Spanish Ministry of Economy and Competitiveness
- European Regional Development Fund (ERDF)
- Obra Social CajAstur-Instituto Universitario de Oncologia del Principado de Asturias
BackgroundWe previously showed that activation of epidermal growth factor receptor (EGFR) induces hypoxia inducible factor-1 (HIF-1) in head and neck squamous cell carcinoma (HNSCC) cells. In this study, we have furthered this by investigating the mechanism of HIF-1 activation by epidermal growth factor (EGF) and its association with the sensitivity to gefitinib. MethodsEGFR/HIF-1 signaling was tested by immunoblot, polymerase chain reaction (PCR), cell proliferation, and apoptosis assays. ResultsHIF-1 accumulated in cells overexpressing EGF and phosphorylated epidermal growth factor receptor (pEGFR), phosphatidylinositol-3-kinase (pPI3K), and mitogen-activated protein kinase (pMAPK). EGF-induced expression of HIF-1 and its targets, vascular endothelial growth factor (VEGF) and BNIP3, were blocked by gefitinib and PI3K-inhibitors and MAPK-inhibitors. HIF-1-siRNAs abrogated EGF-induced BNIP3 but not VEGF expression. Gefitinib inhibited cell proliferation and induced apoptosis more strongly in cells with constitutively active EGFR/HIF-1 signaling than in cells lacking activation of these pathways. HIF-1-siRNA treatment reduced sensitivity to gefitinib. ConclusionThe search for molecular predictors of sensitivity to gefitinib in HNSCC should be extended to the activation status of EGFR-downstream pathways, phosphorylated protein kinase B, pMAPK, and HIF-1. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 1150-1162, 2015
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