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| Status |
Public on Jul 06, 2016 |
| Title |
Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma [shortRNA] |
| Organism |
Homo sapiens |
| Experiment type |
Non-coding RNA profiling by high throughput sequencing
|
| Summary |
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.
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| |
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| Overall design |
Two cell lines, sampled in triplicate.
|
| |
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| Contributor(s) |
Powers JT, Cahan P, Daley GQ |
| Citation(s) |
27383785 |
| Submission date |
May 17, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Patrick Cahan |
| E-mail(s) |
patrick.cahan@jhmi.edu
|
| Organization name |
Johns Hopkins University School of Medicine
|
| Department |
ICE and Biomedical Engineering
|
| Lab |
Cahan Lab
|
| Street address |
733 North Broadway, MRB 653
|
| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21205 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE81500 |
Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma |
|
| Relations |
| BioProject |
PRJNA321945 |
| SRA |
SRP075358 |
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