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Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

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 MYC...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947006/
https://www.ncbi.nlm.nih.gov/pubmed/27383785
http://dx.doi.org/10.1038/nature18632
Descripción
Sumario: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.