Elevated Expression of Fn14 in Non-Small Cell Lung Cancer Correlates with Activated EGFR and Promotes Tumor Cell Migration and Invasion
| Autor: | Timothy G. Whitsett, Emily Cheng, Kaushal Asrani, Jeffrey A. Winkles, Christopher Kingsley, Joseph C. Loftus, Ross M. Bremner, Nhan L. Tran, Galen Hostetter, Glen J. Weiss, Landon J. Inge, Nathan M. Jameson |
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| Rok vydání: | 2012 |
| Předmět: |
Lung Neoplasms
Somatic cell Mice SCID Biology Receptors Tumor Necrosis Factor Pathology and Forensic Medicine Erlotinib Hydrochloride Mice 03 medical and health sciences 0302 clinical medicine Cell Movement Carcinoma Non-Small-Cell Lung Tumor Cells Cultured medicine Animals Humans Neoplasm Invasiveness Epidermal growth factor receptor Phosphorylation Lung cancer Protein Kinase Inhibitors 030304 developmental biology A549 cell 0303 health sciences Gene knockdown Cancer Regular Article medicine.disease Neoplasm Proteins Rats respiratory tract diseases 3. Good health ErbB Receptors Genes ras TWEAK Receptor Gene Knockdown Techniques 030220 oncology & carcinogenesis Mutation Quinazolines Cancer research biology.protein Signal transduction Neoplasm Transplantation Signal Transduction |
| Zdroj: | The American Journal of Pathology. 181:111-120 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2012.03.026 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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