Network modeling of microRNA-mRNA interactions in neuroblastoma tumorigenesis identifies miR-204 as a direct inhibitor of MYCN

Ooi, CY; Carter, DR; Liu, B; Mayoh, C; Beckers, A; Lalwani, A; Nagy, Z; De Brouwer, S; Decaesteker, B; Hung, TT; Norris, MD; Haber, M; Liu, T; De Preter, K; Speleman, F; Cheung, BB; Marshall, GM

Network modeling of microRNA-mRNA interactions in neuroblastoma tumorigenesis identifies miR-204 as a direct inhibitor of MYCN

Ooi, CY Carter, DR Liu, B Mayoh, C Beckers, A Lalwani, A Nagy, Z De Brouwer, S Decaesteker, B Hung, TT Norris, MD Haber, M Liu, T De Preter, K Speleman, F Cheung, BB Marshall, GM

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Publication Type:: Journal Article
Citation:: Cancer Research, 2018, 78 (12), pp. 3122 - 3134
Issue Date:: 2018-06-15

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Field	Value	Language
dc.contributor.author	Ooi, CY	en_US
dc.contributor.author	Carter, DR	en_US
dc.contributor.author	Liu, B	en_US
dc.contributor.author	Mayoh, C	en_US
dc.contributor.author	Beckers, A	en_US
dc.contributor.author	Lalwani, A	en_US
dc.contributor.author	Nagy, Z	en_US
dc.contributor.author	De Brouwer, S	en_US
dc.contributor.author	Decaesteker, B	en_US
dc.contributor.author	Hung, TT	en_US
dc.contributor.author	Norris, MD	en_US
dc.contributor.author	Haber, M	en_US
dc.contributor.author	Liu, T	en_US
dc.contributor.author	De Preter, K	en_US
dc.contributor.author	Speleman, F	en_US
dc.contributor.author	Cheung, BB	en_US
dc.contributor.author	Marshall, GM	en_US
dc.date.issued	2018-06-15	en_US
dc.identifier.citation	Cancer Research, 2018, 78 (12), pp. 3122 - 3134	en_US
dc.identifier.issn	0008-5472	en_US
dc.identifier.uri	http://hdl.handle.net/10453/133116
dc.description.abstract	© 2018 American Association for Cancer Research. Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma.Onthe basis of a Bayesian learning network model in which wecompared pretumor ganglia from TH-MYCN+/+ mice to age-matched wildtype controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis. Significance: Network modeling of miRNA-mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN.	en_US
dc.relation.ispartof	Cancer Research	en_US
dc.relation.isbasedon	10.1158/0008-5472.CAN-17-3034	en_US
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.classification	Oncology & Carcinogenesis	en_US
dc.title	Network modeling of microRNA-mRNA interactions in neuroblastoma tumorigenesis identifies miR-204 as a direct inhibitor of MYCN	en_US
dc.type	Journal Article
utslib.citation.volume	12	en_US
utslib.citation.volume	78	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access	*
pubs.issue	12	en_US
pubs.publication-status	Published	en_US
pubs.volume	78	en_US

Abstract:

© 2018 American Association for Cancer Research. Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma.Onthe basis of a Bayesian learning network model in which wecompared pretumor ganglia from TH-MYCN+/+ mice to age-matched wildtype controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis. Significance: Network modeling of miRNA-mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN.

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http://hdl.handle.net/10453/133116