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FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion

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Abstract

The five-year survival rate in advanced non-small cell lung cancer (NSCLC) remains below ten percent. The invasive and metastatic nature of NSCLC tumor cells contributes to the high mortality rate, and as such the mechanisms that govern NSCLC metastasis is an active area of investigation. Two surface receptors that influence NSCLC invasion and metastasis are the hepatocyte growth factor receptor (HGFR/MET) and fibroblast growth factor-inducible 14 (FN14). MET protein is over-expressed in NSCLC tumors and associated with poor clinical outcome and metastasis. FN14 protein is also elevated in NSCLC tumors and positively correlates with tumor cell migration and invasion. In this report, we show that MET and FN14 protein expressions are significantly correlated in human primary NSCLC tumors, and the protein levels of MET and FN14 are elevated in metastatic lesions relative to patient-matched primary tumors. In vitro, HGF/MET activation significantly enhances FN14 mRNA and protein expression. Importantly, depletion of FN14 is sufficient to inhibit MET-driven NSCLC tumor cell migration and invasion in vitro. This work suggests that MET and FN14 protein expressions are associated with the invasive and metastatic potential of NSCLC. Receptor-targeted therapeutics for both MET and FN14 are in clinical development, the use of which may mitigate the metastatic potential of NSCLC.

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Acknowledgments

We would like to thank Serdar Tuncali, Andrew Nelson, Irene Cherni, and Guy Raz for technical assistance and Drs. Hideo Yagita and Jennifer Michaelson (Biogen Idec) for providing the FN14 monoclonal antibody. This work was supported in part by the NIH grant, R01 CA130940 (N.L.T.), and grants from the St, Joseph’s Foundation and American Lung Association, RG-224607-N (L.J.I.).

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Authors and Affiliations

  1. Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), 445 N. Fifth St., Suite 400, Phoenix, AZ, 85004, USA

    Timothy G. Whitsett, Shannon P. Fortin Ensign, Harshil D. Dhruv, Paul Kurywchak, Kerri K. Wolf, Glen J. Weiss & Nhan L. Tran

  2. Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA

    Shannon P. Fortin Ensign

  3. Center for Thoracic Disease and Transplantation, Heart and Lung Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

    Landon J. Inge

  4. Integrated Cancer Genomics Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    Janine LoBello

  5. Diabetes, Cardiovascular and Metabolic Diseases Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    Christopher B. Kingsley

  6. Humboldt Medical Specialists, Eureka, CA, USA

    Jeffrey W. Allen

  7. Cancer Treatment Centers of America, Goodyear, AZ, USA

    Glen J. Weiss

Authors
  1. Timothy G. Whitsett
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  2. Shannon P. Fortin Ensign
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  3. Harshil D. Dhruv
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  4. Landon J. Inge
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  6. Kerri K. Wolf
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  7. Janine LoBello
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  8. Christopher B. Kingsley
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  9. Jeffrey W. Allen
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  10. Glen J. Weiss
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  11. Nhan L. Tran
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Correspondence to Timothy G. Whitsett or Nhan L. Tran.

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Whitsett, T.G., Fortin Ensign, S.P., Dhruv, H.D. et al. FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion. Clin Exp Metastasis 31, 613–623 (2014). https://doi.org/10.1007/s10585-014-9653-6

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  • DOI: https://doi.org/10.1007/s10585-014-9653-6

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