Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

• Published in: Nature (London) Vol. 535; no. 7611; pp. 246 - 251
• Main Authors: Powers, John T., Tsanov, Kaloyan M., Pearson, Daniel S., Roels, Frederik, Spina, Catherine S., Ebright, Richard, Seligson, Marc, de Soysa, Yvanka, Cahan, Patrick, Theißen, 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-07-2016; Nature Publishing Group
• Subjects: 3' Untranslated Regions - genetics; 38; 38/77; 38/91; 45; 631/208/68; 631/337/384/331; 631/67/68; 692/699/67/2332; 82; 82/1; Animals; Binding sites; Biosynthesis; Cancer; Cell growth; Chromosome Deletion; Chromosomes; Female; Gene Amplification - genetics; Gene Deletion; Genes, Neoplasm - genetics; Genetic aspects; Health aspects; Humanities and Social Sciences; Humans; Mice; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Genetic; multidisciplinary; Mutation; N-Myc Proto-Oncogene Protein; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - pathology; Nuclear Proteins - genetics; Oncogene Proteins - genetics; Pathogenesis; Prognosis; Protein expression; Proteins; RNA-Binding Proteins - genetics; Rodents; Science; Tumors; Xenograft Model Antitumor Assays; Massachusetts
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature18632

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.
Disparate modes of suppression of the
let-7
microRNA family are selectively and inversely related in neuroblastoma.
A unifying pathogenic mechanism for neuroblastoma
The
MYCN
gene acts as a neuroblastoma master oncogene, and its oncogenic role is regulated by the tumour suppressor microRNA
let-7
. The
let-7
inhibitor
LINB28
has been proposed to contribute to
MYCN
oncogenesis. This report uncovers a novel regulatory layer whereby high levels of
MYCN
messenger RNA can act as a sponge for
let-7
, bypassing the need for
LIN28B
negative regulation. In human neuroblastoma development,
let-7
disruption can be achieved by diverse non-overlapping mechanisms including genetic loss,
LIN28B
disruption, or
MYCN
amplification, suggesting an important role in pathogenesis.