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Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Region Östergötland.
Region Östergötland.
Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. (Linköping Integrative Regenerative Medicine Centre)
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2017 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 5Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
M D P I AG , 2017. Vol. 18, no 5
Keyword [en]
HIF-1α; cancer stem cells (CSC); cetuximab; cisplatin; epithelial-mesenchymal transition (EMT); head and neck tumors; hypoxia; radiotherapy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-137276DOI: 10.3390/ijms18050943ISI: 000404113900050PubMedID: 28468237Scopus ID: 2-s2.0-85018414799OAI: oai:DiVA.org:liu-137276DiVA: diva2:1094431
Note

Funding agenceis: County Council of Ostergotland; Research Funds of Linkoping University Hospital; Cancer Foundation of Ostergotland; Swedish Cancer Society; Swedish Research Council

Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-08-07Bibliographically approved

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Wiechec, EmiliaJönsson, Jan-IngvarRoberg, Karin
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Division of Cell BiologyFaculty of Medicine and Health SciencesRegion ÖstergötlandDepartment of Otorhinolaryngology in Linköping
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