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Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors.

ABSTRACT: MicroRNAs are small non-coding RNAs which mediate post-transcriptional gene regulation. Recently, microRNAs have also been found to be localized to the extracellular space, often encapsulated in secreted extracellular vesicles (EVs). This tandem of EVs and tissue-specific expressed/secreted microRNAs that can be taken up by neighboring or distant recipient cells, leading to changes in gene expression-suggests a cell-specialized role in physiological and pathological conditions. The complexity of solid tumors and their distinct pathophysiology relies on interactive communications between the various cell types in the neoplasm (tumor, endothelial, or macrophages, for instance). Understanding how such EV/microRNA-mediated communication occurs may actually lead to avenues for therapeutic exploitation and/or intervention, particularly for the most formidable cancers, such as those in the brain. In this review, the role of microRNAs/EVs in brain tumors will be discussed with emphasis on how these molecules could be utilized for tumor therapy.

SUBMITTER: Bronisz A

PROVIDER: S-EPMC5570546 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Project description:Aging is associated with adipose tissue dysfunction and is recognized as a risk factor for shortened life span. Considering that in vitro findings have shown the involvement of microRNA in extracellular vesicles and particles (EVPs) on senescence, we hypothesized that circulating EVPs derived from adipocytes can be involved in the aging process via their microRNA cargo. We aimed to determine the microRNA profiles of circulating EVPs derived from adipocytes (FABP4+) from aged and young adult animals and to perform in silico prediction of their downstream signaling effects. Plasma was obtained from Wistar rats (3 and 21 months old), and adipocyte-derived EVPs were isolated using the commercially available kit. Fatty acid-binding protein 4 (FABP4) was used for adipocyte-derived EVPs isolation; microRNA isolation and microarray expression analysis were performed. The analysis revealed 728 miRNAs, 32 were differentially between groups (p < 0.05; fold change ≥ |1.1|), of which 15 miRNAs were upregulated and 17 were downregulated in circulating EVPs from aged animals compared to young adults. A conservative filter was applied, and 18 microRNAs had experimentally validated and highly conserved predicted mRNA targets, with a total of 2,228 mRNAs. Canonical pathways, disease and functions, and upstream regulator analyses were performed using IPA-QIAGEN, allowing a global and interconnected evaluation. IPA categories impacted negatively were cell cycle, cellular development, cellular growth and proliferation, and tissue development, while those impacted positively were "digestive system cancer" and "endocrine gland tumor." Interestingly, the upregulated miR-15-5p targets several cyclins, such as CCND1 and CCND2, and miR-24-3p seems to target CDK4 (cyclin-dependent kinase 4); then potentially inhibiting their expression, both miRNAs can induce a negative regulation of cell cycle progression. In contrast, silencing of negative cell cycle checkpoint regulators, such as p21 and p16, can be predicted, which can induce impairment in response to genotoxic stressors. In addition, predicted targets, such as SMAD family members, seem to be involved in the positive control of digestive and endocrine tumors. Taken together, this exploratory study indicates that miRNA signature in circulating adipocyte-derived EVPs may be involved with the double-edged sword of cellular senescence, including irreversible proliferation arrest and tissue-dependent cancer, and seems to be suitable for further validation and confirmatory studies.

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Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors.

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