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.
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Authors | Anneleen 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 |
Journal | Cancer letters
(Cancer Lett)
Vol. 366
Issue 1
Pg. 123-32
(Sep 28 2015)
ISSN: 1872-7980 [Electronic] Ireland |
PMID | 26123663
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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