EGFR through STAT3 modulates ΔN63α expression to sustain tumor-initiating cell proliferation in squamous cell carcinomas

Authors

  • Francesca Ripamonti,

    1. Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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  • Luisa Albano,

    1. Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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  • Anna Rossini,

    1. Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy
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  • Serena Borrelli,

    1. Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Milano, Italy
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  • Sonia Fabris,

    1. Dipartimento di Scienze Cliniche e Comunità, Università di Milano e Ematologia 1 CTMO, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
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  • Roberto Mantovani,

    1. Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Milano, Italy
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  • Antonino Neri,

    1. Dipartimento di Scienze Cliniche e Comunità, Università di Milano e Ematologia 1 CTMO, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
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  • Andrea Balsari,

    1. Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy
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  • Alessandra Magnifico,

    1. Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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  • Elda Tagliabue

    Corresponding author
    1. Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
    • Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan, Italy.
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  • The authors report no declaration of interest.

  • Francesca Ripamonti and Luisa Albano contributed equally to this work.

Abstract

Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the ΔNp63α isoform. Here, we investigated the regulation of ΔNp63α expression upon EGFR activation and the role of the EGFR–ΔNp63α axis in proliferation of SCC tumor-initiating cells (TICs). SCC cell lines A-431, Cal-27, and SCC-25 treated with EGF showed a time-dependent increase in ΔNp63α expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating ΔNp63α expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or ΔNp63α impaired the TICs ability to grow under non-differentiating conditions. Radiation treatment, which triggers EGFR activation, induced ΔNp63α accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non-differentiating conditions. Together, our findings provide evidence that ΔNp63α expression is regulated by EGFR activation through STAT3 and that the EGFR–ΔNp63α axis is crucial for proliferation of TICs present in SCCs. J. Cell. Physiol. 228: 871–878, 2013. © 2012 Wiley Periodicals, Inc.

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