Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

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Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

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Title: Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma
Author: Powers, John T; Tsanov, Kaloyan M; Pearson, Daniel S; Roels, Frederik; Spina, Catherine S; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Theiβen, Jessica; Tu, Ho-Chou; Han, Areum; Kurek, Kyle C; LaPier, Grace S; Osborne, Jihan K; Ross, Samantha J; Cesana, Marcella; Collins, James J; Berthold, Frank; Daley, George Q

Note: Order does not necessarily reflect citation order of authors.

Citation: Powers, J. T., K. M. Tsanov, D. S. Pearson, F. Roels, C. S. Spina, R. Ebright, M. Seligson, et al. 2016. “Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.” Nature 535 (7611): 246-251. doi:10.1038/nature18632.
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Abstract: Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis.
Published Version: doi:10.1038/nature18632
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