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Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

Glioblastoma (GBM) is the most frequent and most malignant primary brain tumour in adults. GBMs have a unique landscape of somatic copy number alterations (SCNAs), with the concomitant appearance of numerous driver amplifications and deletions. Here, we examined the genomic regions harbouring SCNAs...

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Autores principales: Nawaz, Zahid, Patil, Vikas, Thinagararjan, Sivaarumugam, Rao, Soumya A., Hegde, Alangar S., Arivazhagan, Arimappamagan, Santosh, Vani, Somasundaram, Kumaravel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537698/
https://www.ncbi.nlm.nih.gov/pubmed/28378523
http://dx.doi.org/10.1002/1878-0261.12060
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author Nawaz, Zahid
Patil, Vikas
Thinagararjan, Sivaarumugam
Rao, Soumya A.
Hegde, Alangar S.
Arivazhagan, Arimappamagan
Santosh, Vani
Somasundaram, Kumaravel
author_facet Nawaz, Zahid
Patil, Vikas
Thinagararjan, Sivaarumugam
Rao, Soumya A.
Hegde, Alangar S.
Arivazhagan, Arimappamagan
Santosh, Vani
Somasundaram, Kumaravel
author_sort Nawaz, Zahid
collection PubMed
description Glioblastoma (GBM) is the most frequent and most malignant primary brain tumour in adults. GBMs have a unique landscape of somatic copy number alterations (SCNAs), with the concomitant appearance of numerous driver amplifications and deletions. Here, we examined the genomic regions harbouring SCNAs and their impact on the GBM miRNome. We found that 40% of SCNA events covering 70–88% of the genomically altered regions, as identified by GISTIC and RAE algorithms, carried miRNA genes. Of 1426 annotated mature miRNAs analysed, ~ 14% (n = 198) were mapped to such fragile loci. Further, we identified an intragenic miRNA, miR‐4484 located on chromosome‐10, as a deleted and downregulated miRNA in GBM. miR‐4484 exhibited a strong positive correlation with the expression of its host gene uroporphyrinogen III synthase (UROS), thereby indicating that the loss of miR‐4484 is a codeletion event in GBM. Overexpression of miR‐4484 reduced the colony‐forming ability and suppressed the migratory capacity of glioma cells. Analysis of the RNA‐seq‐derived transcriptome upon exogenous miR‐4484 overexpression in conjunction with an integrative bioinformatics approach revealed several putative targets of miR‐4484. Unbiased functional enrichment of these targets through DAVID identified a cohort of important gene ontology terms, which possibly explain the functional role of miR‐4484 in gliomagenesis. Selected targets were validated and, importantly, were found to be upregulated in GBM. In brief, our study identified a panel of miRNAs that are likely to be regulated by genomic deletions and amplifications. Further, miR‐4484 was found to be deleted and acts as a tumour suppressor miRNA in GBM.
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spelling pubmed-55376982017-08-15 Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor Nawaz, Zahid Patil, Vikas Thinagararjan, Sivaarumugam Rao, Soumya A. Hegde, Alangar S. Arivazhagan, Arimappamagan Santosh, Vani Somasundaram, Kumaravel Mol Oncol Research Articles Glioblastoma (GBM) is the most frequent and most malignant primary brain tumour in adults. GBMs have a unique landscape of somatic copy number alterations (SCNAs), with the concomitant appearance of numerous driver amplifications and deletions. Here, we examined the genomic regions harbouring SCNAs and their impact on the GBM miRNome. We found that 40% of SCNA events covering 70–88% of the genomically altered regions, as identified by GISTIC and RAE algorithms, carried miRNA genes. Of 1426 annotated mature miRNAs analysed, ~ 14% (n = 198) were mapped to such fragile loci. Further, we identified an intragenic miRNA, miR‐4484 located on chromosome‐10, as a deleted and downregulated miRNA in GBM. miR‐4484 exhibited a strong positive correlation with the expression of its host gene uroporphyrinogen III synthase (UROS), thereby indicating that the loss of miR‐4484 is a codeletion event in GBM. Overexpression of miR‐4484 reduced the colony‐forming ability and suppressed the migratory capacity of glioma cells. Analysis of the RNA‐seq‐derived transcriptome upon exogenous miR‐4484 overexpression in conjunction with an integrative bioinformatics approach revealed several putative targets of miR‐4484. Unbiased functional enrichment of these targets through DAVID identified a cohort of important gene ontology terms, which possibly explain the functional role of miR‐4484 in gliomagenesis. Selected targets were validated and, importantly, were found to be upregulated in GBM. In brief, our study identified a panel of miRNAs that are likely to be regulated by genomic deletions and amplifications. Further, miR‐4484 was found to be deleted and acts as a tumour suppressor miRNA in GBM. John Wiley and Sons Inc. 2017-05-24 2017-08 /pmc/articles/PMC5537698/ /pubmed/28378523 http://dx.doi.org/10.1002/1878-0261.12060 Text en © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Nawaz, Zahid
Patil, Vikas
Thinagararjan, Sivaarumugam
Rao, Soumya A.
Hegde, Alangar S.
Arivazhagan, Arimappamagan
Santosh, Vani
Somasundaram, Kumaravel
Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor
title Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor
title_full Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor
title_fullStr Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor
title_full_unstemmed Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor
title_short Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor
title_sort impact of somatic copy number alterations on the glioblastoma mirnome: mir‐4484 is a genomically deleted tumour suppressor
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537698/
https://www.ncbi.nlm.nih.gov/pubmed/28378523
http://dx.doi.org/10.1002/1878-0261.12060
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