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MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma.

Abstract
LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3'UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefore establishing an MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promoter, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underline the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process.
AuthorsAnneleen Beckers, Gert Van Peer, Daniel R Carter, Moritz Gartlgruber, Carl Herrmann, Saurabh Agarwal, Hetty H Helsmoortel, Kristina Althoff, Jan J Molenaar, Belamy B Cheung, Johannes H Schulte, Yves Benoit, Jason M Shohet, Frank Westermann, Glenn M Marshall, Jo Vandesompele, Katleen De Preter, Frank Speleman
JournalCancer letters (Cancer Lett) Vol. 366 Issue 1 Pg. 123-32 (Sep 28 2015) ISSN: 1872-7980 [Electronic] Ireland
PMID26123663 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • LIN28B protein, human
  • MIRN26A microRNA, human
  • MYCN protein, human
  • MicroRNAs
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • RNA-Binding Proteins
Topics
  • Cell Line, Tumor
  • Humans
  • MicroRNAs (genetics)
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma (pathology)
  • Nuclear Proteins (physiology)
  • Oncogene Proteins (physiology)
  • RNA-Binding Proteins (genetics)
  • Transcription, Genetic

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