Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Patrick Cahan
PROVIDER: E-GEOD-81500 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project 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. Three cell lines, sampled in triplicate.
2016-07-06 | E-GEOD-81498 | biostudies-arrayexpress
Project 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
2016-07-06 | E-GEOD-81497 | biostudies-arrayexpress
Project 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. Two cell lines, sampled in triplicate.
2016-07-06 | E-GEOD-81499 | biostudies-arrayexpress
Project description:The transcription factor RUNX1 is frequently mutated in myelodysplastic syndrome and leukemia. RUNX1 mutations can be early events, creating pre-leukemic stem cells that expand in the bone marrow. Here we show that, counter-intuitively, Runx1 deficient hematopoietic stem and progenitor cells (HSPCs) have a slow growth, low biosynthetic, small cell phenotype and markedly reduced ribosome biogenesis (Ribi). The reduced Ribi involves decreased levels of rRNA and many mRNAs encoding ribosome proteins. Runx1 appears to directly regulate Ribi; Runx1 is enriched on the promoters of genes encoding ribosome proteins, and binds the ribosomal DNA repeats. Runx1 deficient HSPCs have lower p53 levels, reduced apoptosis, an attenuated unfolded protein response, and accordingly are resistant to genotoxic and endoplasmic reticulum stress. The low biosynthetic activity and corresponding stress resistance provides a selective advantage to Runx1 deficient HSPCs, allowing them to expand in the bone marrow and outcompete normal HSPCs. Comparison of the phenotypic and molecular properties of normal (Runx1f/f, or WT) versus Runx1 deficient (Mut) hematopoietic stem cells.
2015-07-27 | E-GEOD-67609 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-07-06 | GSE81500 | GEO
Project 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.
2016-07-06 | GSE81498 | GEO
Project 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.
2016-07-06 | GSE81497 | GEO
Project 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.
2016-07-06 | GSE81499 | GEO
Project description: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.
| S-EPMC4947006 | biostudies-literature
Project description:Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma
| PRJNA321826 | ENA