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β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

Oncogene volume 30, pages 4087–4096 (2011)Cite this article

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Abstract

Lung cancer is the leading cause of cancer death worldwide. The epidermal growth factor receptor (EGFR) represents the main target for non-small cell lung cancer (NSCLC) therapy, as its overexpression or constitutive activation contributes to malignancy and correlates with poor prognosis. Our previous work demonstrated that in epithelial cells β1 integrin is required for propagating EGFR signaling from the plasma membrane to the nucleus. In this study, we silenced β1 integrin in human NSCLC A549 cells. The β1 integrin-silenced cells show a defective activation of the EGFR signaling cascade, leading to decreased in vitro proliferation, enhanced sensitivity to cisplatin and Gefitinib, impaired migration and invasive behavior. Inhibitory effects on tumor growth and on the EGFR pathway were also observed in in vivo experiments. Moreover, β1 integrin silencing increases the amount of EGFR on the cell surface, suggesting that β1 integrin is required for efficient constitutive EGFR turnover at the cell membrane. Although the rate of EGF internalization and recycling is not affected in silenced cells, EGFR signaling is recovered only by expression of the Rab-coupling protein RCP, indicating that β1 integrin sustains the endocytic machinery required for EGFR signaling. Overall, these results show that β1 integrin is an essential regulator of EGFR signaling and tumorigenic properties of lung cancer cells, and that its silencing might represent an adjuvant approach to anti-EGFR therapy.

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Acknowledgements

We thank Dr Jim Norman (The Beatson Institute for Cancer Research, Glasgow, UK) for kindly providing the RCP construct. We also thank Elona Saraci for initial experiments and Giusy Tornillo for the 3D invasion assays. This work was supported by AIRC, AICR, EU FP7 Metafight, MUR (PRIN, ex-60%), Regione Piemonte—Progetti Sanità, Oncoprot, PiSTEM, Druidi and CIPE, Compagnia San Paolo, Torino.

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Authors and Affiliations

  1. Molecular Biotechnology Center, University of Torino, Torino, Italy

    V Morello, S Cabodi, M P Camacho-Leal, D Repetto, E Turco & P Defilippi

  2. Istituto FIRC di Oncologia Molecolare, Milano

    S Sigismund

  3. Dip Scienze Cliniche E Biologiche, University of Torino, Orbassano (TO), Italy

    M Volante & M Papotti

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  1. V Morello
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Correspondence to P Defilippi.

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Morello, V., Cabodi, S., Sigismund, S. et al. β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells. Oncogene 30, 4087–4096 (2011). https://doi.org/10.1038/onc.2011.107

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