title: Neuron navigator 3 alterations in nervous system tumors associate with tumor malignancy grade and prognosis.
abstract: Copy number changes or reduced expression of the Neuron navigator 3 (NAV3) gene occurs in neuroblastomas and malignancies of epithelial or lymphoid origin. To elucidate whether NAV3 has a role in the tumorigenesis of nervous system tumors in general, we studied central and peripheral nervous system tumors for NAV3 copy number changes. In search for common tumorigenic denominators, we analyzed 113 central and peripheral nervous system tumors, including glial tumors (grades I-IV gliomas), medulloblastomas, and neuroblastomas. NAV3 copy number changes were studied by fluorescence in situ hybridization and correlated to survival analyses. To identify target genes of NAV3 deletion, NAV3 was silenced by siRNA in glioblastoma cell lines and gene expression profiles were analyzed by Agilent 4×44k dual-color microarrays. Selected upregulations were confirmed by immunohistochemistry and quantitative polymerase chain reaction. We found NAV3 amplifications to dominate in neuronally differentiated tumors, whereas glial tumors showed almost equal proportions of NAV3 deletion and amplification. However, Grade IV gliomas had more frequent NAV3 deletions than grades I-III gliomas. Silencing of NAV3 in glioma cell lines led to the upregulation of receptor genes associated with gonadotropin-releasing hormone and Jak-Stat signaling pathways. Kaplan-Meier analysis of the entire clinical tumor material showed association between NAV3 amplifications and favorable prognosis, as well as NAV3 deletions and unfavorable prognosis. With Cox regression model, a hazard ratio of 0.51 was observed for NAV3 amplifications and 1.36 for NAV3 deletions. We conclude that NAV3 may be a potential new prognostic biomarker and a potential therapeutic target.
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, HUS FI-00029, Finland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Carlsson
authors.forename: Kai
authors.initials: K
authors.lastname: Krohn
authors.forename: Kristian
authors.initials: K
authors.lastname: Ovaska
authors.forename: Pia
authors.initials: P
authors.lastname: Lindberg
authors.forename: Valtteri
authors.initials: V
authors.lastname: Häyry
authors.forename: Pilvi
authors.initials: P
authors.lastname: Maliniemi
authors.forename: Anu
authors.initials: A
authors.lastname: Lintulahti
authors.forename: Miikka
authors.initials: M
authors.lastname: Korja
authors.forename: Riku
authors.initials: R
authors.lastname: Kivisaari
authors.forename: Samer
authors.initials: S
authors.lastname: Hussein
authors.forename: Seppo
authors.initials: S
authors.lastname: Sarna
authors.forename: Kirsi
authors.initials: K
authors.lastname: Niiranen
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D034622:RNA Interference; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; C484844:GNRHR protein, human; C515500:IL23R protein, human; D008565:Membrane Proteins; C464453:NAV3 protein, human; D009419:Nerve Tissue Proteins; D018123:Receptors, Interleukin; D011966:Receptors, LHRH