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Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

Oncogene volume 22, pages 6183–6193 (2003)Cite this article

Abstract

Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-α) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-α and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.

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Acknowledgements

This work was supported by EDRN grant (U01CA84968) to J R Grandis and J M Siegfried, NCI Lung cancer SPORE grant (P50CA90440 and R01CA79882) to J M Siegfried and Lung SPORE post-doctoral fellowship to V W Y Lui and S M Thomas.

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  1. Vivian Wai Yan Lui and Sufi Mary Thomas: Co-first authorship

Authors and Affiliations

  1. Departments of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA

    Vivian Wai Yan Lui, Sufi Mary Thomas, Abbey Lynn Wentzel, Joyce Yan Li & Jennifer Rubin Grandis

  2. Deaprtment of pharmacology, University of Pittsburgh Cancer Institute, Pittsburgh, 15213, PA, USA

    Qing Zhang, Jill Marie Siegfried & Jennifer Rubin Grandis

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  1. Vivian Wai Yan Lui
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Correspondence to Jennifer Rubin Grandis.

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Lui, V., Thomas, S., Zhang, Q. et al. Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. Oncogene 22, 6183–6193 (2003). https://doi.org/10.1038/sj.onc.1206720

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