An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma

Sumazin, Pavel; Yang, Xuerui; Chiu, Hua-Sheng; Chung, Wei-Jen; Iyer, Archana; Llobet‐Navas, David; Rajbhandari, Presha; Bansal, Mukesh; Guarnieri, Paolo; Silva, Fernando; Califano, Andrea

doi:10.1016/j.cell.2011.09.041

Cited by 657 publications

(690 citation statements)

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“…Over the last few years, we have pioneered computational and experimental methods for the accurate dissection of tissue-and cell-specific molecular interaction networks, including those controlling transcriptional(protein-DNA) [10,11,16,17], post-transcriptional(RNA-RNA and protein-RNA) [18][19][20][21], signal transduction and other posttranslational processes protein-protein interactions (PPI and metabolic) [22][23][24][25][26], and drug interactions [27][28][29][30]. These methods and datasets allow for the reconstruction of the regulatory and signaling logic of specific cell types by combining specific knowledge about regulatory mechanisms (e.g.…”

Section: Creating the Assembly Manual Of The Alzheimer's Cellmentioning

confidence: 99%

A Systems Approach to Drug Discovery in Alzheimer's Disease

et al. 2015

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In the articles included in this volume, one feels a strong frustration among the writers with the slow course of therapeutics development for Alzheimer's disease and with the clinical failure of targeted therapeutic agents despite substantial progress in our understanding of the biology and biochemistry of the disease. Keywords Master regulator . Interactome . Human neuronsTo date, approaches to Alzheimer disease (AD) therapeutics have followed 2 main avenues. The first addresses neurotransmitter deficits in the early phases of the disease. This approach has led to the handful of AD drugs currently on the market that provide short-term symptomatic improvement but do not alter the course of the disease. The second approach has been directed at decreasing the burden of beta-amyloid (Aβ) in the brain by active or passive immunization or by inhibiting activity of β-or γ-secretases. To date, none of the approaches in this second class has been successful, although trials on β-or γ-secretase (BACE) inhibitors are ongoing.The lack of overt success has been even more frustrating because, in transgenic (Aβ-overproducing) mouse models of AD, Aβ-lowering approaches, as well as treatments with small molecules and biologics, have been successful in blocking memory loss, restoring memory function, reversing dendritic spine alterations, and reversing inhibition of longterm potentiation [1][2][3]. Indeed, as animal models only partially recapitulate the human AD phenotype and because human brain tissue is available only postmortem, translation of preclinical findings to the clinics has been fraught with difficulties.For instance, the characteristic intraneuronal neurofibrillary tangles and extensive neuronal loss observed in human AD are absent in mouse models of the disease. This dichotomy suggests that mouse models replicate only presymptomatic AD stages, while clinical manifestations appear only after neuronal loss becomes irreversible. This hypothesis is directly addressed by ongoing trials, where individuals with genetic mutations that predispose to early AD onset are being treated with Aβ-targeted therapies to assess whether presymptomatic treatment may block an otherwise certain disease progression. Beyond Aβ-targeted therapies, novel approaches are being developed based on inhibition of tau phosphorylation and aggregation, and on blockade of synaptic loss, leveraging "candidate" target approaches derived from human and animal data. Unfortunately, it has so far been impossible to discern whether "candidate genes" represent causal determinants of the disease process or are the downstream result of them.In this review, we will discuss the potential of adapting integrative systems biology approaches that have already proven extremely valuable in understanding multiple cancer related phenotypes to human neurodegenerative diseases.

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Section: Creating the Assembly Manual Of The Alzheimer's Cellmentioning

confidence: 99%

A Systems Approach to Drug Discovery in Alzheimer's Disease

et al. 2015

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“…The miRNA expression profiles vary from one type of cancer to another (Volinia et al 2006). Some upregulated miRNAs can function as oncogenes by inhibiting tumor suppressor genes or other genes that modulate cell differen tia tion and apoptosis, to stimulate cell proliferation, vasculogenesis, and tumorigenesis (Sumazin et al 2011). By contrast, some downregulated miRNAs may act as cancer inhibitors by negatively modulating oncogenes or genes that inhibit cell differentiation and apoptosis (Iorio and Croce 2009).…”

Section: Introductionmentioning

confidence: 99%

Serum Levels of miR-19b and miR-146a as Prognostic Biomarkers for Non-Small Cell Lung Cancer

Cao

et al. 2014

Tohoku J. Exp. Med.

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MicroRNA (miRNA) is a type of small non-coding RNA molecule that has important roles in cancer initiation, promotion and progression by negatively regulating gene expression. In this study, we explored the role of miRNAs in the prognosis of patients with non-small cell lung cancer (NSCLC). The miRNA expression profiles were determined in 5 pairs of NSCLC and paracancerous tissues (3 adenocarcinomas and 2 squamous cell carcinomas). Aberrantly expressed miRNAs were validated by quantitative real-time PCR (qRT-PCR) in 61 pairs of NSCLC and paracancerous tissues. Differentially expressed miRNAs were further analyzed in sera from 94 healthy subjects and 94 advanced NSCLC patients receiving platinumbased chemotherapy. Three miRNAs (miR-19b, miR-146a, and miR-223) were significantly dysregulated in NSCLC tissues (P < 0.05). High miR-19b and low miR-146a expression in NSCLC tissues were associated with higher TNM stage, lymph node metastasis and poorer survival (P < 0.05). The serum levels of miR-19b in NSCLC patients were significantly higher (P < 0.001), whereas serum levels of miR-146a were significantly lower (P < 0.001), compared with those in controls. Serum levels of miR-19b and miR-146a were associated with overall survival of NSCLC patients (P < 0.05). Patients with low serum level of miR-19b and high serum level of miR-146a achieved a higher overall response rate and longer survival time (P < 0.05). These data suggest that miR-19b and miR-146a are potential biomarkers for the prediction of survival and response to chemotherapy in NSCLC.

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“…In mammalian cells, the perfect pairing of miRNA to target RNAs causes RNA cleavage through the RNA interference (RNAi) pathway, whereas partial pairing results in translational repression and RNA destabilization (1,2). miRNA-mediated regulation can be triggered by only 6-nt complementarity of the miRNA 5′-end "seed region" to the target RNA, which confers each miRNA species the capacity to interact with multiple RNA species, including gene-coding mRNAs (3,4), long noncoding RNAs (5), and circular RNAs (6). Similarly, each RNA species can interact with multiple miRNA species through various miRNA response elements (MREs) (7).…”

mentioning

confidence: 99%

Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit

Yuan

Liu

Xie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

106

102

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Competing endogenous RNAs (ceRNAs) cross-regulate each other at the posttranscriptional level by titrating shared microRNAs (miRNAs). Here, we established a computational model to quantitatively describe a minimum ceRNA network and experimentally validated our model predictions in cultured human cells by using synthetic gene circuits. We demonstrated that the range and strength of ceRNA regulation are largely determined by the relative abundance and the binding strength of miRNA and ceRNAs. We found that a nonreciprocal competing effect between partially and perfectly complementary targets is mainly due to different miRNA loss rates in these two types of regulations. Furthermore, we showed that miRNA-like off targets with high expression levels and strong binding sites significantly diminish the RNA interference efficiency, but the effect caused by high expression levels could be compensated by introducing more small interference RNAs (siRNAs). Thus, our results provided a quantitative understanding of ceRNA cross-regulation via shared miRNA and implied an siRNA design strategy to reduce the siRNA off-target effect in mammalian cells. RNAs that are loaded onto RNA-induced silencing complexes (RISC) and subsequently bind to their target RNAs. In mammalian cells, the perfect pairing of miRNA to target RNAs causes RNA cleavage through the RNA interference (RNAi) pathway, whereas partial pairing results in translational repression and RNA destabilization (1, 2). miRNA-mediated regulation can be triggered by only 6-nt complementarity of the miRNA 5′-end "seed region" to the target RNA, which confers each miRNA species the capacity to interact with multiple RNA species, including gene-coding mRNAs (3, 4), long noncoding RNAs (5), and circular RNAs (6). Similarly, each RNA species can interact with multiple miRNA species through various miRNA response elements (MREs) (7).The complex interaction network of miRNAs and their target RNAs has been shown to allow indirect cross-regulation between different competing endogenous RNAs (ceRNAs) by sequestering shared miRNAs, which is essential for regulating many biological functions (7). The strength of ceRNA regulation is largely determined by the relative abundance and binding strength of ceRNAs and miRNAs and whether the miRNA-bound ceRNA decays through a stoichiometric mechanism or a catalytic mechanism (8-10). The threshold-like behavior of the ceRNA regulation has been experimentally observed by measuring the abundance of two ceRNAs, phosphatase and tensin homolog (PTEN) and vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) across various cell lines (8). Nevertheless, many quantitative predictions deduced from miRNA-ceRNA computational models have not been experimentally validated. Another intriguing question is whether the miRNA-mediated catalytic mechanism can be affected by the miRNA-mediated stoichiometric mechanism through a ceRNA effect or vice versa.Currently, the ability to systematically elucidate features of the ceRNA effect is impeded by th...

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An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma

Cited by 657 publications

References 42 publications

A Systems Approach to Drug Discovery in Alzheimer's Disease

A Systems Approach to Drug Discovery in Alzheimer's Disease

Serum Levels of miR-19b and miR-146a as Prognostic Biomarkers for Non-Small Cell Lung Cancer

Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit

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