title: Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome.
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-kappaB (NF-kappaB) activity. The Fn14 promoter region contains NF-kappaB 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.
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.forename: Wendy S
authors.initials: WS
authors.lastname: McDonough
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Savitch
authors.forename: Shannon P
authors.initials: SP
authors.lastname: Fortin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.forename: Marc
authors.initials: M
authors.lastname: Symons
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Heather E
authors.initials: HE
authors.lastname: Cunliffe
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.forename: Dominique B
authors.initials: DB
authors.lastname: Hoelzinger
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Rennert
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lipinski
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000074050:TWEAK Receptor; D014162:Transfection; D016896:Treatment Outcome; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613300:Tnfrsf12a protein, rat; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D020830:rac1 GTP-Binding Protein