Pei Y Liu1, Daniela Erriquez1, Glenn M Marshall1, Andrew E Tee1, Patsie Polly1, Mathew Wong1, Bing Liu1, Jessica L Bell1, Xu D Zhang1, Giorgio Milazzo1, Belamy B Cheung1, Archa Fox1, Alexander Swarbrick1, Stefan Hüttelmaier1, Maria Kavallaris1, Giovanni Perini1, John S Mattick1, Marcel E Dinger1, Tao Liu2. 1. Affiliations of authors: Children's Cancer Institute Australia for Medical Research, Randwick NSW, Australia (PYL, GMM, AET, MW, BL, BBC, MK, TL); Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy (DE, GM, GP); Kids Cancer Centre, Sydney Children's Hospital, Randwick NSW, Australia (GMM); Department of Pathology and Inflammation and Infection Research Centre, University of New South Wales, Kensington 2052, Australia (PP); Institute of Molecular Medicine, Martin Luther University, ZAMED, Halle, Germany (JLB, SH); School of Medicine and Public Health, Priority Research Centre for Cancer Research, University of Newcastle, Callaghan NSW, Australia (XDZ); Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands WA, Australia (AF); Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst NSW, Australia (AS); St Vincent's Clinical School, University of New South Wales, Darlinghurst NSW, Australia (AS, JSM, MED); Australian Centre for Nanomedicine, Randwick NSW, Australia (MK); Garvan Institute of Medical Research, Darlinghurst NSW, Australia (AS, JSM, MED); School of Women's & Children's Health, University of New South Wales, Randwick NSW, Australia (TL). 2. Affiliations of authors: Children's Cancer Institute Australia for Medical Research, Randwick NSW, Australia (PYL, GMM, AET, MW, BL, BBC, MK, TL); Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy (DE, GM, GP); Kids Cancer Centre, Sydney Children's Hospital, Randwick NSW, Australia (GMM); Department of Pathology and Inflammation and Infection Research Centre, University of New South Wales, Kensington 2052, Australia (PP); Institute of Molecular Medicine, Martin Luther University, ZAMED, Halle, Germany (JLB, SH); School of Medicine and Public Health, Priority Research Centre for Cancer Research, University of Newcastle, Callaghan NSW, Australia (XDZ); Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands WA, Australia (AF); Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst NSW, Australia (AS); St Vincent's Clinical School, University of New South Wales, Darlinghurst NSW, Australia (AS, JSM, MED); Australian Centre for Nanomedicine, Randwick NSW, Australia (MK); Garvan Institute of Medical Research, Darlinghurst NSW, Australia (AS, JSM, MED); School of Women's & Children's Health, University of New South Wales, Randwick NSW, Australia (TL). tliu@ccia.unsw.edu.au.
Abstract
BACKGROUND: Patients with neuroblastoma due to the amplification of a 130-kb genomic DNA region containing the MYCN oncogene have poor prognoses. METHODS: Bioinformatics data were used to discover a novel long noncoding RNA, lncUSMycN, at the 130-kb amplicon. RNA-protein pull-down assays were used to identify proteins bound to lncUSMycN RNA. Kaplan-Meier survival analysis, multivariable Cox regression, and two-sided log-rank test were used to examine the prognostic value of lncUSMycN and NonO expression in three cohorts of neuroblastoma patients (n = 47, 88, and 476, respectively). Neuroblastoma-bearing mice were treated with antisense oligonucleotides targeting lncUSMycN (n = 12) or mismatch sequence (n = 13), and results were analyzed by multiple comparison two-way analysis of variance. All statistical tests were two-sided. RESULTS: Bioinformatics data predicted lncUSMycN gene and RNA, and reverse-transcription polymerase chain reaction confirmed its three exons and two introns. The lncUSMycN gene was coamplified with MYCN in 88 of 341 human neuroblastoma tissues. lncUSMycN RNA bound to the RNA-binding protein NonO, leading to N-Myc RNA upregulation and neuroblastoma cell proliferation. High levels of lncUSMycN and NonO expression in human neuroblastoma tissues independently predicted poor patient prognoses (lncUSMycN: hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.06 to 3.28, P = .03; NonO: HR = 2.48, 95% CI = 1.34 to 4.57, P = .004). Treatment with antisense oligonucleotides targeting lncUSMycN in neuroblastoma-bearing mice statistically significantly hindered tumor progression (P < .001). CONCLUSIONS: Our data demonstrate the important roles of lncUSMycN and NonO in regulating N-Myc expression and neuroblastoma oncogenesis and provide the first evidence that amplification of long noncoding RNA genes can contribute to tumorigenesis.
BACKGROUND:Patients with neuroblastoma due to the amplification of a 130-kb genomic DNA region containing the MYCN oncogene have poor prognoses. METHODS: Bioinformatics data were used to discover a novel long noncoding RNA, lncUSMycN, at the 130-kb amplicon. RNA-protein pull-down assays were used to identify proteins bound to lncUSMycN RNA. Kaplan-Meier survival analysis, multivariable Cox regression, and two-sided log-rank test were used to examine the prognostic value of lncUSMycN and NonO expression in three cohorts of neuroblastomapatients (n = 47, 88, and 476, respectively). Neuroblastoma-bearing mice were treated with antisense oligonucleotides targeting lncUSMycN (n = 12) or mismatch sequence (n = 13), and results were analyzed by multiple comparison two-way analysis of variance. All statistical tests were two-sided. RESULTS: Bioinformatics data predicted lncUSMycN gene and RNA, and reverse-transcription polymerase chain reaction confirmed its three exons and two introns. The lncUSMycN gene was coamplified with MYCN in 88 of 341 humanneuroblastoma tissues. lncUSMycN RNA bound to the RNA-binding protein NonO, leading to N-Myc RNA upregulation and neuroblastoma cell proliferation. High levels of lncUSMycN and NonO expression in humanneuroblastoma tissues independently predicted poor patient prognoses (lncUSMycN: hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.06 to 3.28, P = .03; NonO: HR = 2.48, 95% CI = 1.34 to 4.57, P = .004). Treatment with antisense oligonucleotides targeting lncUSMycN in neuroblastoma-bearing mice statistically significantly hindered tumor progression (P < .001). CONCLUSIONS: Our data demonstrate the important roles of lncUSMycN and NonO in regulating N-Myc expression and neuroblastoma oncogenesis and provide the first evidence that amplification of long noncoding RNA genes can contribute to tumorigenesis.
Authors: Nadia Vadie; Sheena Saayman; Alexandra Lenox; Amanda Ackley; Mathew Clemson; Jon Burdach; Jonathan Hart; Peter K Vogt; Kevin V Morris Journal: RNA Biol Date: 2015 Impact factor: 4.652
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Authors: Mike R Russell; Annalise Penikis; Derek A Oldridge; Juan R Alvarez-Dominguez; Lee McDaniel; Maura Diamond; Olivia Padovan; Pichai Raman; Yimei Li; Jun S Wei; Shile Zhang; Janahan Gnanchandran; Robert Seeger; Shahab Asgharzadeh; Javed Khan; Sharon J Diskin; John M Maris; Kristina A Cole Journal: Cancer Res Date: 2015-06-22 Impact factor: 12.701