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Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation

Oncogene volume 29, pages 5135–5145 (2010)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors.

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Acknowledgements

This work was supported by Grants RO1 CA77308, RO1 CA101840 and P50 CA097190, and an American Cancer Society Clinical Research professorship CRP-08-229-01 (to JRG) and the NIH core Grant EY08098.

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Author notes

  1. S Y Lai

    Present address: 7Current address: Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.,

  2. S E Wheeler and S Suzuki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    S E Wheeler, S Suzuki, S M Thomas, M Sen, S Y Lai & J R Grandis

  2. Department Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    R J Leeman-Neill & S I Chiosea

  3. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    C-T Kuan & D D Bigner

  4. Department Biostatistics, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    W E Gooding

  5. Department Pharmacology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    J R Grandis

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  1. S E Wheeler
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Wheeler, S., Suzuki, S., Thomas, S. et al. Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation. Oncogene 29, 5135–5145 (2010). https://doi.org/10.1038/onc.2009.279

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