Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-κB and correlate with poor patient outcome

Nhan Tran, Wendy S. McDonough, Benjamin A. Savitch, Shannon P. Fortin, Jeffrey A. Winkles, Marc Symons, Mitsutoshi Nakada, Heather E. Cunliffe, Galen Hostetter, Dominique B. Hoelzinger, Jessica L. Rennert, Jennifer S. Michaelson, Linda C. Burkly, Christopher A. Lipinski, Joseph C Loftus, Luigi Mariani, Michael E. Berens

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

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-κB (NF-κB) activity. The Fn14 promoter region contains NF-κB 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.

Original languageEnglish (US)
Pages (from-to)9535-9542
Number of pages8
JournalCancer Research
Volume66
Issue number19
DOIs
StatePublished - Oct 1 2006

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Glioma
Biochemical Phenomena
Genetic Phenomena
Tumor Necrosis Factor Receptors
Genetic Promoter Regions
Neuroglia
Small Interfering RNA
Cell Movement
fibroblast growth factor 14
Up-Regulation
Central Nervous System
Tumor Necrosis Factor-alpha
Binding Sites
Apoptosis
Ligands
Gene Expression
Survival
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-κB and correlate with poor patient outcome. / Tran, Nhan; McDonough, Wendy S.; Savitch, Benjamin A.; Fortin, Shannon P.; Winkles, Jeffrey A.; Symons, Marc; Nakada, Mitsutoshi; Cunliffe, Heather E.; Hostetter, Galen; Hoelzinger, Dominique B.; Rennert, Jessica L.; Michaelson, Jennifer S.; Burkly, Linda C.; Lipinski, Christopher A.; Loftus, Joseph C; Mariani, Luigi; Berens, Michael E.

In: Cancer Research, Vol. 66, No. 19, 01.10.2006, p. 9535-9542.

Research output: Contribution to journalArticle

Tran, N, McDonough, WS, Savitch, BA, Fortin, SP, Winkles, JA, Symons, M, Nakada, M, Cunliffe, HE, Hostetter, G, Hoelzinger, DB, Rennert, JL, Michaelson, JS, Burkly, LC, Lipinski, CA, Loftus, JC, Mariani, L & Berens, ME 2006, 'Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-κB and correlate with poor patient outcome', Cancer Research, vol. 66, no. 19, pp. 9535-9542. https://doi.org/10.1158/0008-5472.CAN-06-0418
Tran, Nhan ; McDonough, Wendy S. ; Savitch, Benjamin A. ; Fortin, Shannon P. ; Winkles, Jeffrey A. ; Symons, Marc ; Nakada, Mitsutoshi ; Cunliffe, Heather E. ; Hostetter, Galen ; Hoelzinger, Dominique B. ; Rennert, Jessica L. ; Michaelson, Jennifer S. ; Burkly, Linda C. ; Lipinski, Christopher A. ; Loftus, Joseph C ; Mariani, Luigi ; Berens, Michael E. / Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-κB and correlate with poor patient outcome. In: Cancer Research. 2006 ; Vol. 66, No. 19. pp. 9535-9542.
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AU - Nakada, Mitsutoshi

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