Oncotarget

Research Papers:

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

Chia-Lang Hsu, Hsin-Yi Chang, Jen-Yun Chang, Wen-Ming Hsu, Hsuan-Cheng Huang _ and Hsueh-Fen Juan

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Oncotarget. 2016; 7:36293-36310. https://doi.org/10.18632/oncotarget.9202

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Abstract

Chia-Lang Hsu1, Hsin-Yi Chang1, Jen-Yun Chang1, Wen-Ming Hsu2, Hsuan-Cheng Huang3, Hsueh-Fen Juan1

1Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan

2Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan

3Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 112, Taiwan

Correspondence to:

Hsuan-Cheng Huang, email: [email protected]

Hsueh-Fen Juan, email: [email protected]

Keywords: genomics, neuroblastoma, MYCN, regulatory network, microRNA

Received: February 28, 2016     Accepted: April 19, 2016     Published: May 06, 2016

ABSTRACT

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 regulatory networks. The overall analysis indicated that MYCN-regulated genes were involved in a wide range of biological processes and could be used as signatures to identify poor-prognosis MYCN-non-amplified patients. Analysis of the MYCN binding sites showed that MYCN principally served as an activator. Using a computational approach, we identified 32 MYCN co-regulators, and some of these findings are supported by previous studies. Moreover, we investigated the interplay between MYCN transcriptional and microRNA post-transcriptional regulations and identified several microRNAs, such as miR-124-3p and miR-93-5p, which may significantly contribute to neuroblastoma pathogenesis. We also found MYCN and its regulated microRNAs acted together to repress the tumor suppressor genes. This work provides a comprehensive view of MYCN regulations for exploring therapeutic targets in neuroblastoma, as well as insights into the mechanism of neuroblastoma tumorigenesis.


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