Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

NOTCH3 is a master-regulator of motility in neuroblastoma and is essential for cell survival

ABSTRACT: Migratory embryonal neuroblasts give rise to several tissues, including the sympathetic nervous system (SNS). Neuroblastomas are paediatric tumours of the peripheral SNS with a highly variable prognosis. We observed that high NOTCH3 expression in neuroblastomas correlated with a poor prognosis. Expression of a NOTCH3 transgene in neuroblastoma cells induced many motility genes and conferred a highly motile phenotype. Expression of these motility genes strongly correlated with NOTCH3 expression in neuroblastomas and many other tumours, suggesting a general role for NOTCH3 in regulation of these genes. Silencing of NOTCH3 or genes of the Notch-processing M-NM-3-secretase complex induced apoptosis in all neuroblastoma cell lines tested. These data suggest that NOTCH3 is a key-regulator of motility, and indispensable for survival of neuroblastoma cells. Time-course experiments of NOTCH3IC induction in two independent clones (c6 and c8), with 9 or 8 time points, respectively.

ORGANISM(S): Homo sapiens

SUBMITTER: Rogier Versteeg

PROVIDER: E-GEOD-16477 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A NOTCH3 transcriptional module induces cell motility in neuroblastoma.

van Nes Johan J Chan Alvin A van Groningen Tim T van Sluis Peter P Koster Jan J Versteeg Rogier R

Clinical cancer research : an official journal of the American Association for Cancer Research 20130506 13

<h4>Purpose</h4>Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system with an often lethal outcome due to metastatic disease. Migration and epithelial-mesenchymal transitions have been implicated in metastasis but they are hardly investigated in neuroblastoma.<h4>Experimental design</h4>Cell migration of 16 neuroblastoma cell lines was quantified in Transwell migration assays. Gene expression profiling was used to derive a migration signature, which was applied to class ...[more]

PMID: 23649002

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Project description:Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor-driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box transcription factor FOXR1. Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of forkhead-box factor mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in over-expression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma. Time series Affymetrix U133p2 profiling of Osteosarcoma HOS cells transduced with FOXR1 targeted shRNAs or control shRNA

Dataset Information

NOTCH3 is a master-regulator of motility in neuroblastoma and is essential for cell survival

Publications

A NOTCH3 transcriptional module induces cell motility in neuroblastoma.

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