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Molecular and Cellular Pathobiology

A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma

Jason M. Shohet, Rajib Ghosh, Cristian Coarfa, Andrew Ludwig, Ashley L. Benham, Zaowen Chen, Danielle M. Patterson, Eveline Barbieri, Pieter Mestdagh, Denae N. Sikorski, Aleksandar Milosavljevic, Eugene S. Kim and Preethi H. Gunaratne
Jason M. Shohet
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Rajib Ghosh
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Cristian Coarfa
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Andrew Ludwig
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Ashley L. Benham
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Zaowen Chen
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Danielle M. Patterson
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Eveline Barbieri
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Pieter Mestdagh
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Denae N. Sikorski
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Aleksandar Milosavljevic
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Eugene S. Kim
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Preethi H. Gunaratne
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DOI: 10.1158/0008-5472.CAN-10-4391
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Abstract

MYCN is a major driver of neuroblastoma tumorigenesis and MYCN amplification is the worst prognostic indicator of aggressive NB. To identify potentially therapeutic tumor suppressor microRNAs for aggressive NB, we utilized a conditional MYCN system to simulate MYCN-amplified and nonamplified tumor types and performed a genome-wide search for MYCN target microRNA promoters differentially repressed under high MYCN conditions. We identified 20 gene promoters hosting 30 microRNAs that were directly bound and differentially regulated by MYCN. Eleven of these genes showed significant clinical correlations for neuroblastoma with 4 genes linked with better survival and 7 genes linked with poor survival. Surprisingly, expression analysis of host genes and microRNAs demonstrated that 8 of 11 pairs were repressed by high levels of MYCN regardless of the clinical correlation of the host gene. We therefore predicted these intronic microRNAs would be tumor suppressors. In fact, detailed gain of function studies for two miRs, miR-591 and miR-558, confirmed potent tumor suppressive effects for miR-591 in orthotopic neuroblastoma xenografts. However, miR-558 markedly increased colony formation, proliferation, and tumor growth in vivo. Our data reveal host-gene independent functions of MYCN-target microRNAs and demonstrate that MYCN represses both tumor suppressive and proproliferative microRNAs. Cancer Res; 71(11); 1–11. ©2011 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received December 5, 2010.
  • Revision received March 4, 2011.
  • Accepted March 22, 2011.
  • ©2011 American Association for Cancer Research.
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Published OnlineFirst May 24, 2011
doi: 10.1158/0008-5472.CAN-10-4391

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A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma
Jason M. Shohet, Rajib Ghosh, Cristian Coarfa, Andrew Ludwig, Ashley L. Benham, Zaowen Chen, Danielle M. Patterson, Eveline Barbieri, Pieter Mestdagh, Denae N. Sikorski, Aleksandar Milosavljevic, Eugene S. Kim and Preethi H. Gunaratne
Cancer Res May 24 2011 DOI: 10.1158/0008-5472.CAN-10-4391

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A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma
Jason M. Shohet, Rajib Ghosh, Cristian Coarfa, Andrew Ludwig, Ashley L. Benham, Zaowen Chen, Danielle M. Patterson, Eveline Barbieri, Pieter Mestdagh, Denae N. Sikorski, Aleksandar Milosavljevic, Eugene S. Kim and Preethi H. Gunaratne
Cancer Res May 24 2011 DOI: 10.1158/0008-5472.CAN-10-4391
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