MiRNA expression profiling in high-risk neuroblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16444 | GEO | 2009/06/27
SECONDARY ACCESSION(S): PRJNA116347
REPOSITORIES: GEO
Similar Datasets
Project description:In the present study we evaluated the miRNA expression profile of 31 high risk, stage 4 neuroblastoma patients. We compared miRNA expression profiles of 14 long-survivors (alive with an overall survival time > 36 months) and 17 short-survivors (dead of disease within 36 months from diagnosis. Deaths due to toxicity were censored).
2010-05-16 | E-GEOD-16444 | biostudies-arrayexpress
Project description:We performed array CGH in high-risk neuroblastoma tumors in order to compare genome aberrations with expression of small non-coding RNAs.
2008-12-31 | GSE14109 | GEO
Project description:High-risk neuroblastoma is a devastating malignancy with few therapeutic options. We identify withaferin A (WA) as a natural ferroptosis inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA targets and inactivates glutathione peroxidase 4, as well as increases intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which both independently result in ferroptosis. This double-edged mechanism results in a high efficacy of WA compared to etoposide in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing neuroblastoma xenografts growth and relapse rate. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced targeting to the tumor site. Collectively, our data propose a novel therapeutic strategy to kill cancer cells by ferroptosis. High-risk neuroblastoma is a devastating malignancy with few therapeutic options. We identify withaferin A (WA) as a natural ferroptosis inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA targets and inactivates glutathione peroxidase 4, as well as increases intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which both independently result in ferroptosis. This double-edged mechanism results in a high efficacy of WA compared to etoposide in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing neuroblastoma xenografts growth and relapse rate. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced targeting to the tumor site. Collectively, our data propose a novel therapeutic strategy to kill cancer cells by ferroptosis.
2018-05-01 | GSE112384 | GEO
Project description:Neuroblastoma is a pediatric cancer of the developing sympathetic nervous system. High-risk neuroblastoma patients typically undergo an initial remission in response to treatment, followed by recurrence of aggressive tumors that have become refractory to further treatment. The need for biomarkers that can select patients not responding well to therapy in an early phase is therefore needed. In this study, we used next generation sequencing technology to determine the expression profiles in high-risk neuroblastoma cell lines established before and after therapy. Using partial least squares-discriminant analysis (PLS-DA) with least absolute shrinkage and selection operator (LASSO) and leave-one-out cross-validation, we identified a panel of 55 messenger RNAs and 17 long non-coding RNAs (lncRNAs) which were significantly altered in the expression between cell lines isolated from primary and recurrent tumors. From a neuroblastoma patient cohort, we found 20 of the 55 protein-coding genes to be differentially expressed in patients with unfavorable compared with favorable outcome. We further found a twofold increase or decrease in hazard ratios in these genes when comparing patients with unfavorable and favorable outcome. Gene set enrichment analysis (GSEA) revealed that these genes were involved in proliferation, differentiation and regulated by Polycomb group (PcG) proteins. Of the 17 lncRNAs, 3 upregulated (NEAT1, SH3BP5-AS1, NORAD) and 3 downregulated lncRNAs (DUBR, MEG3, DHRS4-AS1) were also found to be differentially expressed in favorable compared with unfavorable outcome. Moreover, using expression profiles on both miRNAs and mRNAs in the same cohort of cell lines, we found 13 downregulated and 18 upregulated experimentally observed miRNA target genes targeted by miR-21, -424 and -30e, -29b, -138, -494, -181a, -34a, -29b, respectively. The advantage of analyzing biomarkers in a clinically relevant neuroblastoma model system enables further studies on the effect of individual genes upon gene perturbation. In summary, this study identified several genes, which may aid in the prediction of response to therapy and tumor recurrence.
2020-04-16 | GSE148700 | GEO
Project description:Integrative discovery of treatments for high-risk neuroblastoma
| PRJNA495016 | ENA
Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.
2021-11-24 | GSE164504 | GEO
Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.
2021-11-24 | GSE164505 | GEO
Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with diverse clinical behaviors. Even with multimodal therapies, high-risk neuroblastoma has an unfavorable outcome irrespective of MYCN amplification, a well-established oncogenic driver in neuroblastoma pathogenesis, and its genetic heterogeneity has largely impeded efforts to correlate molecular targets with biological consequences for more effective treatment strategies. Here, using a gene expression-based approach, we identified the FDA-approved anthelmintic niclosamide as a potential anti-neuroblastoma drug. By combining the gene expression signature associated with high-risk neuroblastoma and the recurrent drug−transcript relationships inferred from up to one million perturbational gene expression profiles, our algorithm predicted effective therapeutic candidates by evaluating the extent to which a given compound or their combinations could ‘reverse’ the high-risk signature. Furthermore, we performed quantitative polymerase chain reaction (qPCR) to validate top five candidate reverse genes which are involved in DNA replication, including cyclin A2 (CCNA2), minichromosome maintenance 10 replication initiation factor (MCM10), ERCC excision repair 6 like, spindle assembly checkpoint helicase (ERCC6L), kinesin family member 20A (KIF20A), and RuvB like AAA ATPase 1 (RUVBL1). Indeed, those five genes were downregulated in niclosamide-treated cells, indicating niclosamide suppressed DNA replication and then inhibited cell proliferation. Using cell proliferation and clonogenic assays as well as flow cytometry, we determined the cytotoxic effects of niclosamide in MYCN-amplified SK-N-DZ and non-amplified SK-N-AS cells. The results showed that niclosamide could effectively reduce not only cell proliferation and colony formation but also trigger cell cycle arrest and apoptosis. Moreover, we conducted human tumor xenografts in a nude mice model to evaluate the in vivo efficacy of niclosamide and found that it significantly suppressed tumor growth and prolonged survival rate, but doesn’t cause organ damage and change body weight. To explore the molecular mechanism of niclosamide, stable-isotope dimethyl labeling strategy for quantitative proteomics was performed on both cell-based or xenograft-based MYCN-amplified SK-N-DZ and MYCN-nonamplified SK-N-AS models. We confirmed niclosamide not only mediated the function of mitochondrial electron transport chain but also the other functions in high risk neuroblastoma cell lines and xenografts. The results suggest that our developed expression-based strategy is useful for drug discovery and provides the possibility of repurposing the anthelminthic drug niclosamide for treating high-risk neuroblastoma therapy.
2022-02-23 | PXD010745 | Pride
Project description:Neuroblastoma is the most common solid tumour in childhood and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be particularlysensitive to indisulam, a molecular glue that selectively targets the RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models indisulam induced rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlighted a particular disruption to cell cycle and metabolism. Metabolic profiling demonstrated metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour without relapse was observed in both xenografts and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss confirmed in vivo. Our data imply that dual targeting of metabolism and RNA splicing with anti-cancer sulfonamides such as indisulam is promising therapeutic approach for high-risk neuroblastoma.
2022-01-13 | PXD022164 | Pride
Project description:Purpose: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. (i) Distal 6q losses were detected in 5.9% of patients and were associated with a ten-year survival probability of only 3.4%. (ii) Amplifications of regions not encompassing the MYCN locus were detected in 18% of patients and were associated with a ten-year survival probability of only 5.8%. Conclusion: Using a unique large copy number dataset of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.
2018-03-13 | GSE103123 | GEO