Epidermal growth factor receptor regulates MET levels and invasiveness through hypoxia-inducible factor-1α in non-small cell lung cancer cells

L. Xu, M. B. Nilsson, P. Saintigny, T. Cascone, M. H. Herynk, Z. Du, P. G. Nikolinakos, Y. Yang, L. Prudkin, D. Liu, J. J. Lee, F. M. Johnson, K. K. Wong, L. Girard, A. F. Gazdar, J. D. Minna, J. M. Kurie, I. I. Wistuba, J. V. Heymach

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of non-amplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxia-inducible factor (HIF)-1α pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1α. EGFR-and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1α and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.

Original languageEnglish (US)
Pages (from-to)2616-2627
Number of pages12
JournalOncogene
Volume29
Issue number18
DOIs
StatePublished - May 1 2010

Keywords

  • EGFR
  • HIF-1a
  • Invasiveness
  • MET
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Xu, L., Nilsson, M. B., Saintigny, P., Cascone, T., Herynk, M. H., Du, Z., Nikolinakos, P. G., Yang, Y., Prudkin, L., Liu, D., Lee, J. J., Johnson, F. M., Wong, K. K., Girard, L., Gazdar, A. F., Minna, J. D., Kurie, J. M., Wistuba, I. I., & Heymach, J. V. (2010). Epidermal growth factor receptor regulates MET levels and invasiveness through hypoxia-inducible factor-1α in non-small cell lung cancer cells. Oncogene, 29(18), 2616-2627. https://doi.org/10.1038/onc.2010.16