MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

36 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)123-132
Aantal pagina's10
TijdschriftCancer Letters
Volume366
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 28 sep. 2015
Extern gepubliceerdJa

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