title: MDA-9/syntenin is a key regulator of glioma pathogenesis.
abstract: BACKGROUND
  The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human melanoma models. To determine whether MDA-9/syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis.
  
  
  METHODS
  We assessed MDA-9/syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Through gain-of-function and loss-of-function studies, we analyzed changes in invasion, angiogenesis, and signaling in vitro. We used orthotopic xenografts with GBM6 cells to demonstrate the role of MDA-9/syntenin in GBM pathogenesis in vivo.
  
  
  RESULTS
  MDA-9/syntenin expression in high-grade astrocytomas is significantly higher than normal tissue counterparts. Forced overexpression of MDA-9/syntenin enhanced Matrigel invasion, while knockdown inhibited invasion, migration, and anchorage-independent growth in soft agar. Moreover, overexpression of MDA-9/syntenin increased activation of c-Src, p38 mitogen-activated protein kinase, and nuclear factor kappa-B, leading to elevated expression of matrix metalloproteinase 2 and secretion of interleukin-8 with corresponding changes observed upon knockdown. GBM6 cells that stably express small hairpin RNA for MDA-9/syntenin formed smaller tumors and had a less invasive phenotype in vivo.
  
  
  CONCLUSIONS
  Our findings indicate that MDA-9/syntenin is a novel and important mediator of invasion in GBM and a key regulator of pathogenesis, and we identify it as a potential target for anti-invasive treatment in human astrocytoma.
authors.affiliation: Corresponding author: Paul B. Fisher, MPh, PhD, Professor and Chairman, Department of Human and Molecular Genetics, Director, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, 1101 East Marshall Street, Sanger Hall Building, Room 11-015, Richmond, VA 23298-0033. pbfisher@vcu.edu.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Manny D
authors.initials: MD
authors.lastname: Bacolod
authors.forename: Christine E
authors.initials: CE
authors.lastname: Fuller
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D053676:Syntenins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C109621:SDCBP protein, human; D053676:Syntenins; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: GBM; MDA-9/syntenin; glioma; intracranial injection; invasion