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Therapy-, gender- and race-specific microRNA markers, target genes and networks related to glioblastoma recurrence and survival.

ABSTRACT: To identify and study targets of microRNA biomarkers of glioblastoma survival across events (death and recurrence) and phases (life expectancy or post-diagnostic) using functional and network analyses.microRNAs associated with glioblastoma survival within and across race, gender, recurrence, and therapy cohorts were identified using 253 individuals, 534 microRNAs, Cox survival model, cross-validation, discriminant analyses, and cross-study comparison.All 45 microRNAs revealed as being associated with survival were confirmed in independent cancer studies and 25 in glioblastoma studies. Thirty-nine and six microRNAs (including hsa-miR-222) were associated with one and multiple glioblastoma survival indicators, respectively. Nineteen and 26 microRNAs exhibited cohort-dependent (including hsa-miR-10b with therapy and hsa-miR-486 with race) and independent associations with glioblastoma, respectively.Sensory perception and G protein-coupled receptor processes were enriched among microRNA gene targets also associated with survival and network visualization highlighted their relations. These findings can help to improve prognostic tools and personalized treatments.

SUBMITTER: Delfino KR

PROVIDER: S-EPMC3321577 | biostudies-literature | 2011 Jul-Aug

REPOSITORIES: biostudies-literature

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Therapy-, gender- and race-specific microRNA markers, target genes and networks related to glioblastoma recurrence and survival.

Delfino K R KR Serão N V L NV Southey B R BR Rodriguez-Zas S L SL

Cancer genomics & proteomics 20110701 4

<h4>Aim</h4>To identify and study targets of microRNA biomarkers of glioblastoma survival across events (death and recurrence) and phases (life expectancy or post-diagnostic) using functional and network analyses.<h4>Materials and methods</h4>microRNAs associated with glioblastoma survival within and across race, gender, recurrence, and therapy cohorts were identified using 253 individuals, 534 microRNAs, Cox survival model, cross-validation, discriminant analyses, and cross-study comparison.<h4 ...[more]

PMID: 21737610

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Project description:BackgroundMicroRNAs (miRNAs) mediate posttranscriptional regulation of protein-coding genes by binding to the 3' untranslated region of target mRNAs, leading to translational inhibition, mRNA destabilization or degradation, depending on the degree of sequence complementarity. In general, a single miRNA concurrently downregulates hundreds of target mRNAs. Thus, miRNAs play a key role in fine-tuning of diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. However, it remains to be fully elucidated whether a set of miRNA target genes regulated by an individual miRNA in the whole human microRNAome generally constitute the biological network of functionally-associated molecules or simply reflect a random set of functionally-independent genes.MethodsThe complete set of human miRNAs was downloaded from miRBase Release 16. We explored target genes of individual miRNA by using the Diana-microT 3.0 target prediction program, and selected the genes with the miTG score ≧ 20 as the set of highly reliable targets. Then, Entrez Gene IDs of miRNA target genes were uploaded onto KeyMolnet, a tool for analyzing molecular interactions on the comprehensive knowledgebase by the neighboring network-search algorithm. The generated network, compared side by side with human canonical networks of the KeyMolnet library, composed of 430 pathways, 885 diseases, and 208 pathological events, enabled us to identify the canonical network with the most significant relevance to the extracted network.ResultsAmong 1,223 human miRNAs examined, Diana-microT 3.0 predicted reliable targets from 273 miRNAs. Among them, KeyMolnet successfully extracted molecular networks from 232 miRNAs. The most relevant pathway is transcriptional regulation by transcription factors RB/E2F, the disease is adult T cell lymphoma/leukemia, and the pathological event is cancer.ConclusionThe predicted targets derived from approximately 20% of all human miRNAs constructed biologically meaningful molecular networks, supporting the view that a set of miRNA targets regulated by a single miRNA generally constitute the biological network of functionally-associated molecules in human cells.

Project description:Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.

Dataset Information

Therapy-, gender- and race-specific microRNA markers, target genes and networks related to glioblastoma recurrence and survival.

Publications

Therapy-, gender- and race-specific microRNA markers, target genes and networks related to glioblastoma recurrence and survival.

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