Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Article

关键词: COMPARATIVE GENOMIC HYBRIDIZATION;    COMPETITIVE ENDOGENOUS RNA;    GENE-EXPRESSION;    N-MYC;    CANCER;    TUMOR;    LIN28B;    CELLS;    MIRNA;    AMPLIFICATION;   

DOI  :  10.1038/nature18632

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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