Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RIP-Chip analysis of Musashi (Msi1) in the U251, a human glioma cell line

ABSTRACT: Musashi1 (Msi1) is a highly conserved RNA binding protein that is required during the development of the nervous system. Msi1 has a role in neural stem cells, controlling the balance between self-renewal and differentiation. Msi1 has also been implicated in cancer, being highly expressed in multiple tumor types. In this study, we analyzed Msi1 expression in a large cohort of medulloblastoma samples and showed that Msi1 is highly expressed in tumor tissue compared to normal cerebellum and that high Msi1 expression is associated with a poor prognosis. Using a nude mouse xenograft model, we demonstrate that Msi1 is important for tumor growth. We then used RIP-chip (ribonucleoprotein immunoprecipitation followed by microarray analysis) to identify mRNA targets of Msi1 in medulloblastoma. In conclusion, our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target. RIP-Chip analysis to identify mRNA preferentially associated with Msi1 protein. RIP-Chip experiments were performed on two biologically replicated samples. A total of 8 microarrays were carried on using technical replicates of Msi1 antibody vs. prebleed serum for each dye orientation. We prepared two biological replicates for two different arrays. Each array consisted of 4 microarrays with 2 replicates for each dye orientation.

ORGANISM(S): Homo sapiens

SUBMITTER: raquel abreu

PROVIDER: E-GEOD-37216 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with group 3 (G3) MB representing the most aggressive subgroup associated with a poor prognosis and a remarkable ability to resist upfront multimodal therapy. Despite a low mutational burden of disease and MYC amplification identified as a independent factor associated with poor survivorship, efforts to target the MYC has met with limited therapeutic success. Consequently alternative mediators associated with the aggressive phenotype of G3 MB continues as a common goal within the MB community. Here we show how the neural stem cell determinant Musashi 1 (MSI1) is a central and vital moderator of G3 MB in both a MYC amplified mouse model of G3 MB and patient derived xenografts (PDX). Specifically, we modified the MYC amplified and p53 mutated (MP) mouse model of G3 MB to generate Msi1 conditional knockout mice (Msi1flox/flox), which led to the observation that MSI1 is required for tumor initiation of MP tumors. To identify the translational potential of these findings, we employed shRNA against Msi1 in multiple PDX lines, observing a striking deficit in multiple key stem cell features including self-renewal, proliferation, and failure to progress through the cell cycle. Notably, Msi1 inhibition resulted in a failure of tumor initiation, translating to a significantly prolonged survival, reaffirming the essential role for MSI1 in G3 MB. To determine how MSI1 symphonizes the anarchic post-transcriptional landscape of G3MB, we differentially analyzed the MSI1 binding sites in normal neural stem cells and G3 MB and subsequently compared the MSI1-binding transcriptome, and proteome following Msi1 inhibition. Comparative analysis suggested an integral role for post-transcriptional regulators, such as MSI1 and its binding prey mRNA, as a therapeutic target. Here we propose the neural RNA binding protein MSI1, as a master regulator, hijacked from its normal neural developmental function, orchestrating the aberrant translational landscape of G3 MB.

Dataset Information

RIP-Chip analysis of Musashi (Msi1) in the U251, a human glioma cell line

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