title: Expression of TWEAK/Fn14 in neuroblastoma: implications in tumorigenesis.
abstract: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) family of cytokines, acts on responsive cells via binding to a cell surface receptor called Fn14. TWEAK binding to an Fn14 receptor or constitutive Fn14 overexpression has been shown to activate nuclear factor κB signaling which is important in tumorigenesis and cancer therapy resistance. In the present study, we demonstrate that TWEAK and Fn14 are expressed in neuroblastoma cell lines and primary tumors, and both are observed at increased levels in high-stage tumors. The treatment of neuroblastoma cell lines with recombinant TWEAK in vitro causes increased survival, and this effect is partially due to the activation of NF-κB signaling. Moreover, TWEAK induces the release of matrix metalloprotease-9 (MMP-9) in neuroblastoma cells, suggesting that TWEAK may play a role in the invasive phase of neuroblastoma tumorigenesis. TWEAK-induced cell survival was significantly reduced by silencing the TWEAK and Fn14 gene functions by siRNA. Thus, the expression of TWEAK and Fn14 in neuroblastoma suggests that TWEAK functions as an important regulator of primary neuroblastoma growth, invasion and survival and that the therapeutic intervention of the TWEAK/Fn14 pathway may be an important clinical strategy in neuroblastoma therapy.
authors: Translational Cancer Research Group, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
authors: Ingvild
authors: I
authors: Pettersen
authors: Ninib
authors: N
authors: Baryawno
authors: Frida
authors: F
authors: Abel
authors: Wenche Helen
authors: WH
authors: Bakkelund
authors: Svetlana N
authors: SN
authors: Zykova
authors: Jan-Olof
authors: JO
authors: Winberg
authors: Ugo
authors: U
authors: Moens
authors: Agnes
authors: A
authors: Rasmuson
authors: Per
authors: P
authors: Kogner
authors: John Inge
authors: JI
authors: Johnsen
authors: Baldur
authors: B
authors: Sveinbjörnsson
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D000074049:Cytokine TWEAK; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D004792:Enzyme Precursors; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9