microRNA regulatory network inference identifies miR-34a as a novel regulator of TGF-β signaling in glioblastoma

Genovese, G., Ergun, A., Shukla, S. A., Campos, B., Hanna, J., Ghosh, P., Quayle, S. N., Rai, K., Colla, S., Ying, H., Wu, C. J., Sarkar, S., Xiao, Y., Zhang, J., Zhang, H., Kwong, L., Dunn, K., Wiedemeyer, W. R., Brennan, C., Zheng, H., Rimm, D. L., Collins, J. J., Chin, L. (2012) microRNA regulatory network inference identifies miR-34a as a novel regulator of TGF-β signaling in glioblastoma. Cancer Discovery, 2 (8). pp. 736-749.

URL: http://www.ncbi.nlm.nih.gov/pubmed/22750848
DOI: 10.1158/2159-8290.CD-12-0111

Abstract

Leveraging The Cancer Genome Atlas (TCGA) multidimensional data in glioblastoma, we inferred the putative regulatory network between microRNA and mRNA using the Context Likelihood of Relatedness modeling algorithm. Interrogation of the network in context of defined molecular subtypes identified 8 microRNAs with a strong discriminatory potential between proneural and mesenchymal subtypes. Integrative in silico analyses, a functional genetic screen, and experimental validation identified miR-34a as a tumor suppressor in proneural subtype glioblastoma. Mechanistically, in addition to its direct regulation of platelet-derived growth factor receptor-alpha (PDGFRA), promoter enrichment analysis of context likelihood of relatedness-inferred mRNA nodes established miR-34a as a novel regulator of a SMAD4 transcriptional network. Clinically, miR-34a expression level is shown to be prognostic, where miR-34a low-expressing glioblastomas exhibited better overall survival. This work illustrates the potential of comprehensive multidimensional cancer genomic data combined with computational and experimental models in enabling mechanistic exploration of relationships among different genetic elements across the genome space in cancer. SIGNIFICANCE: We illustrate here that network modeling of complex multidimensional cancer genomic data can generate a framework in which to explore the biology of cancers, leading to discovery of new pathogenetic insights as well as potential prognostic biomarkers. Specifically in glioblastoma, within the context of the global network, promoter enrichment analysis of network edges uncovered a novel regulation of TGF-β signaling via a Smad4 transcriptomic network by miR-34a.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Zheng lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 2012
Date Deposited: 30 Jan 2013 21:45
Last Modified: 16 Oct 2015 13:57
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26946

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