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E-GEOD-81497 - Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma [Let7Targets]

Status
Released on 6 July 2016, last updated on 9 July 2016
Organism
Homo sapiens
Samples (4)
Protocols (4)
Description
The let-7 microRNA families are tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has been implicated as a critical regulator of MYCN ; however, here we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN amplified neuroblastoma cell lines despite robust de-repression of let-7 . We further report that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-set of self-sponging amplified competing endogenous RNA (aceRNA) and reconciles the dispensability of LIN28B . In addition, we observe frequent genomic loss of let-7 that inversely associates with MYCN- amplification, providing an explanation for common, yet unresolved amplification-independent patterns of chromosome loss. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN amplified tumors marks decreased survival, further underscoring its importance. The inverse relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis. BE(2)C:MYCN-ORF cells transfected with siRNA and miRNA mimics
Experiment type
RNA-seq of coding RNA 
Contacts
Patrick Cahan <patrick.cahan@jhmi.edu>, George Q Daley, John T Powers
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
Files
Investigation descriptionE-GEOD-81497.idf.txt
Sample and data relationshipE-GEOD-81497.sdrf.txt
Additional data (1)E-GEOD-81497.additional.1.zip
Links