Journal
CANCER LETTERS
Volume 366, Issue 1, Pages 123-132Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.06.015
Keywords
MicroRNA; Integrative analysis; Cross-species
Categories
Funding
- GOA [01G01910]
- European Union Seventh Framework Programme (FP7-ASSET project) [259348]
- Belgian Foundation Against Cancer (Stichting Tegen Kanker) [SCIE] [2010-177, 2012-199]
- Belgian National Fund for Scientific Research (FWO) [G.0530.12N]
- Belgian Childhood Cancer Fund (vzw Kinderkankerfonds)
- Agency for Innovation by Science and Technology, Flanders (IWT) [IWT 101506]
- Flemish League against Cancer (Vlaamse Liga Tegen Kanker)
- Ghent University [BOF 01D35609]
- FWO
- NHMRC Australia
- Cancer Institute NSW
- Cancer Council NSW
- NIH [R01-CA174808]
- Alex's Lemonade Stand Foundation for Childhood Cancer
- GillsonLongenbaugh Foundation
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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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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