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Int. J. Mol. Sci. 2017, 18(5), 943; doi:10.3390/ijms18050943

Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

1
Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping 581 85, Sweden
2
Department of ENT—Head and Neck Surgery, County Council of Östergötland, Linköping 581 85, Sweden
3
Division of Oto-Rhino-Laryngology and Head & Neck Surgery, Linköping 581 85, Sweden
4
Linköping Integrative Regenerative Medicine Centre, Linköping University, Linköping 581 85, Sweden
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Hiroyuki Tomita, Masahito Shimizu and Takuji Tanaka
Received: 22 February 2017 / Revised: 19 April 2017 / Accepted: 24 April 2017 / Published: 29 April 2017
(This article belongs to the Special Issue Cancer Stem Cells)
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Abstract

Despite advances in the head and neck squamous cell carcinoma (HNSCC) treatment modalities, drug resistance and cancer recurrence are often reported. Hypoxia signaling through hypoxia-inducible factor 1 (HIF-1) promotes angiogenesis and metastasis by inducing epithelial-mesenchymal-transition (EMT). The aim of this study was to evaluate the impact of hypoxia on response to therapy as well as EMT and expression of stem cell markers in HNSCC cells. Five HNSCC cell lines (UT-SCC-2, UT-SCC-14, LK0412, LK0827, and LK0923) were selected for this study. The treatment sensitivity for radiation, cisplatin, cetuximab, and dasatinib was assessed by crystal violet assay. Gene expression of EMT and cancer stem cell (CSC) markers as well as protein level of EGFR signaling molecules were analyzed by qPCR and western blotting, respectively. Unlike UT-SCC-14 and LK0827, the LK0412 cell line became significantly more sensitive to cetuximab in hypoxic conditions. This cetuximab sensitivity was efficiently reversed after suppression of HIF-1α with siRNA. Additionally, hypoxia-induced EMT and expression of stem cell markers in HNSCC cells was partially revoked by treatment with cetuximab or knockdown of HIF-1α. In summary, our study shows that hypoxia might have a positive influence on the anti-EGFR therapy effectiveness in HNSCC. However, due to heterogeneity of HNSCC lesions, targeting HIF-1α may not be sufficient to mediate such a response. Further studies identifying a trait of hypoxia-specific response to cetuximab in HNSCC are advisable. View Full-Text
Keywords: hypoxia; HIF-1α; epithelial-mesenchymal transition (EMT); cancer stem cells (CSC); head and neck tumors; radiotherapy; cetuximab; cisplatin hypoxia; HIF-1α; epithelial-mesenchymal transition (EMT); cancer stem cells (CSC); head and neck tumors; radiotherapy; cetuximab; cisplatin
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MDPI and ACS Style

Wiechec, E.; Hansson, K.T.; Alexandersson, L.; Jönsson, J.-I.; Roberg, K. Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells. Int. J. Mol. Sci. 2017, 18, 943.

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