Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion

Timothy G. Whitsett, Emily Cheng, Landon Inge, Kaushal Asrani, Nathan M. Jameson, Galen Hostetter, Glen J. Weiss, Christopher B. Kingsley, Joseph C. Loftus, Ross Bremner, Nhan L. Tran, Jeffrey A. Winkles

Research output: Contribution to journalArticle

Abstract

Lung cancer is the leading cause of cancer deaths worldwide; approximately 85% of these cancers are non-small cell lung cancer (NSCLC). Patients with NSCLC frequently have tumors harboring somatic mutations in the epidermal growth factor receptor (EGFR) gene that cause constitutive receptor activation. These patients have the best clinical response to EGFR tyrosine kinase inhibitors (TKIs). Herein, we show that fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is frequently overexpressed in NSCLC tumors, and Fn14 levels correlate with p-EGFR expression. We also report that NSCLC cell lines that contain EGFR-activating mutations show high levels of Fn14 protein expression. EGFR TKI treatment of EGFR-mutant HCC827 cells decreased Fn14 protein levels, whereas EGF stimulation of EGFR wild-type A549 cells transiently increased Fn14 expression. Furthermore, Fn14 is highly expressed in EGFR-mutant H1975 cells that also contain an EGFR TKI-resistance mutation, and high TKI doses are necessary to reduce Fn14 levels. Constructs encoding EGFRs with activating mutations induced Fn14 expression when expressed in rat lung epithelial cells. We also report that short hairpin RNA-mediated Fn14 knockdown reduced NSCLC cell migration and invasion in vitro. Finally, Fn14 overexpression enhanced NSCLC cell migration and invasion in vitro and increased experimental lung metastases in vivo. Thus, Fn14 may be a novel therapeutic target for patients with NSCLC, in particular for those with EGFR-driven tumors who have either primary or acquired resistance to EGFR TKIs.

Original languageEnglish (US)
Pages (from-to)111-120
Number of pages10
JournalAmerican Journal of Pathology
Volume181
Issue number1
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    Whitsett, T. G., Cheng, E., Inge, L., Asrani, K., Jameson, N. M., Hostetter, G., Weiss, G. J., Kingsley, C. B., Loftus, J. C., Bremner, R., Tran, N. L., & Winkles, J. A. (2012). Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion. American Journal of Pathology, 181(1), 111-120. https://doi.org/10.1016/j.ajpath.2012.03.026