TY - JOUR
T1 - microRNA regulatory network inference identifies miR-34a as a novel regulator of TGF-β signaling in glioblastoma
AU - Genovese, Giannicola
AU - Ergun, Ayla
AU - Shukla, Sachet A.
AU - Campos, Benito
AU - Hanna, Jason
AU - Ghosh, Papia
AU - Quayle, Steven N.
AU - Rai, Kunal
AU - Colla, Simona
AU - Ying, Haoqiang
AU - Wu, Chang Jiun
AU - Sarkar, Sharmistha
AU - Xiao, Yonghong
AU - Zhang, Jianhua
AU - Zhang, Hailei
AU - Kwong, Lawrence
AU - Dunn, Katherine
AU - Wiedemeyer, Wolf Ruprecht
AU - Brennan, Cameron
AU - Zheng, Hongwu
AU - Rimm, David L.
AU - Collins, James J.
AU - Chin, Lynda
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-12-0111
DO - 10.1158/2159-8290.CD-12-0111
M3 - Article
C2 - 22750848
AN - SCOPUS:84866248155
SN - 2159-8274
VL - 2
SP - 736
EP - 749
JO - Cancer discovery
JF - Cancer discovery
IS - 8
ER -