MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma

A Beckers, G Van Peer, DR Carter, M Gartlgruber… - Cancer letters, 2015 - Elsevier
A Beckers, G Van Peer, DR Carter, M Gartlgruber, C Herrmann, S Agarwal, HH Helsmoortel
Cancer letters, 2015Elsevier
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 …
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.
Elsevier