Multiple Mechanisms Disrupt the Let-7 MicroRNA Family in Neuroblastoma

Overview

Journal Nature

Specialty Science

Date 2016 Jul 8

PMID 27383785

Citations 105

Authors

John T Powers

Kaloyan M Tsanov

Daniel S Pearson

Frederik Roels

Catherine S Spina

Richard Ebright

Marc Seligson

Yvanka de Soysa

Patrick Cahan

Jessica Theissen

Ho-Chou Tu

Areum Han

Kyle C Kurek

Grace S LaPier

Jihan K Osborne

Samantha J Ross

Marcella Cesana

James J Collins

Frank Berthold

George Q Daley

Affiliations

Soon will be listed here.

Abstract

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour 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. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA 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 development with broad implications for cancer pathogenesis.

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