Genome-wide perturbations by miRNAs map onto functional cellular pathways, identifying regulators of chromatin modifiers View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

Tyler J Moss, Zijun Luo, Elena G Seviour, Vasudha Sehgal, Yiling Lu, Steven M Hill, Rajesha Rupaimoole, Ju-Seog Lee, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K Sood, Robert Azencott, Joe W Gray, Sach Mukherjee, Gordon B Mills, Prahlad T Ram

ABSTRACT

BACKGROUND: Regulation of gene expression by microRNAs (miRNAs) is critical for determining cellular fate and function. Dysregulation of miRNA expression contributes to the development and progression of multiple diseases. miRNA can target multiple mRNAs, making deconvolution of the effects of miRNA challenging and the complexity of regulation of cellular pathways by miRNAs at the functional protein level remains to be elucidated. Therefore, we sought to determine the effects of expression of miRNAs in breast and ovarian cancer cells on cellular pathways by measuring systems-wide miRNA perturbations to protein and phosphoproteins. METHODS: We measure protein level changes by reverse-phase protein array (RPPA) in MDA-MB-231, SKOV3.ip1 and HEYA8 cancer cell lines transfected by a library of 879 human miRNA mimics. RESULTS: The effects of multiple miRNAs-protein networks converged in five broad functional clusters of miRNA, suggesting a broad overlap of miRNA action on cellular pathways. Detailed analysis of miRNA clusters revealed novel miRNA/cell cycle protein networks, which we functionally validated. De novo phosphoprotein network estimation using Gaussian graphical modeling, using no priors, revealed known and novel protein interplay, which we also observed in patient ovarian tumor proteomic data. We identified several miRNAs that have pluripotent activities across multiple cellular pathways. In particular we studied miR-365a whose expression is associated with poor survival across several cancer types and demonstrated that anti-miR-365 significantly reduced tumor formation in animal models. CONCLUSIONS: Mapping of miRNA-induced protein and phosphoprotein changes onto pathways revealed new miRNA-cellular pathway connectivity, paving the way for targeting of dysregulated pathways with potential miRNA-based therapeutics. More... »

PAGES

15001

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/npjsba.2015.1

DOI

http://dx.doi.org/10.1038/npjsba.2015.1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1047321951

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28725457


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Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

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curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/npjsba.2015.1'

N-Triples is a line-based linked data format ideal for batch operations.

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Turtle is a human-readable linked data format.

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RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/npjsba.2015.1'


 

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