microRNA Regulatory Network Inference Identifies miR-34a as a Novel Regulator of TGF- Signaling in Glioblastoma

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Cancer Discovery (Impact Factor: 19.45). 06/2012; 2(8):736-49. DOI: 10.1158/2159-8290.CD-12-0111
Source: PubMed


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.

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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Available from: Wolf Ruprecht Wiedemeyer, Dec 29, 2015
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    • "Figure 2 shows the GBM-BioDP profile of mir-34a. Consistent with Genovese et al.’s [26] findings, mir-34a is overexpressed across GBM samples – zscores of the majority of the samples are above 1.5 (Figure 2A, C). Moreover, proneural samples show significantly lower expression of mir-34a compared to the other types of GBM (pairwise t-test p-values for proneural versus other subtypes are 0, Figure 2B, 2C). "
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    ABSTRACT: Validation of clinical biomarkers and response to therapy is a challenging topic in cancer research. An important source of information for virtual validation is the datasets generated from multi-center cancer research projects such as The Cancer Genome Atlas project (TCGA). These data enable investigation of genetic and epigenetic changes responsible for cancer onset and progression, response to cancer therapies, and discovery of the molecular profiles of various cancers. However, these analyses often require bulk download of data and substantial bioinformatics expertise, which can be intimidating for investigators. Here, we report on the development of a new resource available to scientists: a data base called Glioblastoma Bio Discovery Portal (GBM-BioDP). GBM-BioDP is a free web-accessible resource that hosts a subset of the glioblastoma TCGA data and enables an intuitive query and interactive display of the resultant data. This resource provides visualization tools for the exploration of gene, miRNA, and protein expression, differential expression within the subtypes of GBM, and potential associations with clinical outcome, which are useful for virtual biological validation. The tool may also enable generation of hypotheses on how therapies impact GBM molecular profiles, which can help in personalization of treatment for optimal outcome. The resource can be accessed freely at (a tutorial is included).
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    • "miR-34a causes cell cycle arrest and apoptosis in cancer stem cells [53] via p53. miR-34a was also reported to target Notch signaling pathway to inhibit tumor stem cell invasion by directly binding to NOTCH1, DLL1 and JAG1 [54], [55] as well as Wnt signaling pathway by targeting WNT1 and WNT3 genes [53], [56] and TGF-β signaling pathway via Smad4 [57]. In our study, Tp53 and miR-34a were upregulated, hence could inhibit Notch, Wnt and TGF-β signaling by targeting Dll1, Jag1, Wnt1, Wnt3 and Smad4. "
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    ABSTRACT: To date, miRNA expression studies on cerebral ischemia in both human and animal models have focused mainly on acute phase of ischemic stroke. In this study, we present the roles played by microRNAs in the spontaneous recovery phases in cerebral ischemia using rodent stroke models. Brain tissues were harvested at different reperfusion time points ranging from 0-168 hrs after middle cerebral artery occlusion using homologous emboli. MiRNA and mRNA expression profiles were investigated by microarray followed by multiple statistical analysis. Candidate transcripts were also validated by quantitative RT-PCR. Three specific groups of miRNAs were observed among a total of 346 differentially expressed miRNAs. miRNAs, miR-21, -142-3p, -142-5p, and -146a displayed significant upregulation during stroke recovery (48 hrs to 168 hrs) compared with those during acute phases (0 hrs to 24 hrs). On the other hand, an opposite trend was observed in the expression of miR-196a/b/c, -224 and -324-3p. Interestingly, miR-206, -290, -291a-5p and -30c-1*, positively correlated with the infarct sizes, with an initial increase up to 24hrs followed by a gradual decrease from 48 hrs to 168 hrs (R = 0.95). Taken together with the expression levels of corresponding mRNA targets, we have also found that Hedgehog, Notch, Wnt and TGF-β signaling pathways could play significant roles in stroke recovery and especially in neuronal repair.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "miR-34a, which is induced by p53, is considered to be a key regulator of tumor-suppressive signaling pathways in various cancers (Bader, 2012). Furthermore, recent reports have revealed that miR-34a plays a crucial role in the molecular pathogenesis of GBM (Li et al., 2009), although the function is more complex in GBM and remains under investigation (Genovese et al., 2012; Silber et al., 2012; Yin et al., 2012). Replacement therapy of miR-34a is an attractive approach for various malignant tumors, but should be introduced carefully for GBM. "
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    ABSTRACT: Glioblastoma (GBM) is one of the most common and dismal brain tumors in adults. Further elucidation of the molecular pathogenesis of GBM is mandatory to improve the overall survival of patients. A novel small non-coding RNA molecule, microRNA (miRNA), appears to represent one of the most attractive target molecules contributing to the pathogenesis of various types of tumors. Recent global analyses have revealed that several miRNAs are clinically implicated in GBM, with some reports indicating the association of miRNA dysregulation with acquired temozolomide (TMZ) resistance. More recent studies have revealed that miRNAs could play a role in cancer stem cell (CSC) properties, contributing to treatment resistance. In addition, greater impact might be expected from miRNA-targeted therapies based on tumor-derived exosomes that contain numerous functional miRNAs, which could be transferred between tumor cells and surrounding structures. Tumor-derived miRNAs are now considered to be a novel molecular mechanism promoting the progression of GBM. Establishment of miRNA-targeted therapies based on miRNA dysregulation of CSCs could provide effective therapeutic strategies for TMZ-resistant GBM. Recent progress has revealed that miRNAs are not only putative biological markers for diagnosis, but also one of the most promising targets for GBM treatment. Here in, we summarize the translational aspects of miRNAs in the diagnosis and treatment of GBM.
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