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Increased Fibroblast Growth Factor-Inducible 14 Expression Levels Promote Glioma Cell Invasion via Rac1 and Nuclear Factor-B and Correlate with Poor Patient Outcome

¹ Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona; ² Departments of Surgery and Physiology and the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; ³ Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-Long Island Jewish Health System, Manhasset, New York; ⁴ Biogen Idec, Inc., Cambridge, Massachusetts; ⁵ Mayo Clinic Scottsdale, Scottsdale, Arizona; and ⁶ University Hospital, Inselspital, Bern, Switzerland

Requests for reprints: Michael E. Berens, Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004. Phone: 602-343-8760; Fax: 602-343-8844; E-mail: mberens{at}tgen.org.

Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion throughout the central nervous system. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. Our current report shows that the fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Forced Fn14 overexpression stimulates glioma cell migration and invasion, and depletion of Rac1 by small interfering RNA inhibits this cellular response. Activation of Fn14 signaling by the ligand TNF-like weak inducer of apoptosis (TWEAK) stimulates migration and up-regulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor-B (NF-B) activity. The Fn14 promoter region contains NF-B binding sites, which mediate positive feedback causing sustained overexpression of Fn14 and enduring glioma cell invasion. Furthermore, Fn14 gene expression levels increase with glioma grade and inversely correlate with patient survival. These results show that the Fn14 cascade operates as a positive feedback mechanism for elevated and sustained Fn14 expression. Such a feedback loop argues for aggressive targeting of the Fn14 axis as a unique and specific driver of glioma malignant behavior. (Cancer Res 2006; 66(19): 9535-42)

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