Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Effects of MYCN knockdwon on miRNA expression in neuroblastoma cells

ABSTRACT: Global miRNAs expression profilling of SK-N-BE(2)-C cells after dsRNA-mediated knockdown of MYCN To identify MYCN-associated miRNAs, we carried out a small RNA-seq on MYCN knockdown in SK-N-BE(2)-C cells to profile the miRNA expression.

ORGANISM(S): Homo sapiens

SUBMITTER: Hsueh-Fen Juan

PROVIDER: E-GEOD-72721 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data.

Hsu Chia-Lang CL Chang Hsin-Yi HY Chang Jen-Yun JY Hsu Wen-Ming WM Huang Hsuan-Cheng HC Juan Hsueh-Fen HF

Oncotarget 20160601 24

MYCN, an oncogenic transcription factor of the Myc family, is a major driver of neuroblastoma tumorigenesis. Due to the difficulty in drugging MYCN directly, revealing the molecules in MYCN regulatory networks will help to identify effective therapeutic targets for neuroblastoma therapy. Here we perform ChIP-sequencing and small RNA-sequencing of neuroblastoma cells to determine the MYCN-binding sites and MYCN-associated microRNAs, and integrate various types of genomic data to construct MYCN re ...[more]

PMID: 27167114

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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.

Dataset Information

Effects of MYCN knockdwon on miRNA expression in neuroblastoma cells

Publications

Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data.

Similar Datasets

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