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The miR-17-92 microRNA cluster regulates multiple components of the TGF-? pathway in neuroblastoma.

ABSTRACT: The miR-17-92 microRNA cluster is often activated in cancer cells, but the identity of its targets remains elusive. Using SILAC and quantitative mass spectrometry, we examined the effects of activation of the miR-17-92 cluster on global protein expression in neuroblastoma (NB) cells. Our results reveal cooperation between individual miR-17-92 miRNAs and implicate miR-17-92 in multiple hallmarks of cancer, including proliferation and cell adhesion. Most importantly, we show that miR-17-92 is a potent inhibitor of TGF-? signaling. By functioning both upstream and downstream of pSMAD2, miR-17-92 activation triggers downregulation of multiple key effectors along the TGF-? signaling cascade as well as direct inhibition of TGF-?-responsive genes.

SUBMITTER: Mestdagh P

PROVIDER: S-EPMC3032380 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma.

Mestdagh Pieter P Boström Anna-Karin AK Impens Francis F Fredlund Erik E Van Peer Gert G De Antonellis Pasqualino P von Stedingk Kristoffer K Ghesquière Bart B Schulte Stefanie S Dews Michael M Thomas-Tikhonenko Andrei A Schulte Johannes H JH Zollo Massimo M Schramm Alexander A Gevaert Kris K Axelson Håkan H Speleman Frank F Vandesompele Jo J

Molecular cell 20101201 5

The miR-17-92 microRNA cluster is often activated in cancer cells, but the identity of its targets remains elusive. Using SILAC and quantitative mass spectrometry, we examined the effects of activation of the miR-17-92 cluster on global protein expression in neuroblastoma (NB) cells. Our results reveal cooperation between individual miR-17-92 miRNAs and implicate miR-17-92 in multiple hallmarks of cancer, including proliferation and cell adhesion. Most importantly, we show that miR-17-92 is a po ...[more]

PMID: 21145484

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Project description:Multipotent mesenchymal stromal cell (MSC) harvested exosomes are hypothesized as the major paracrine effectors of MSCs. In vitro, the miR-17-92 cluster promotes oligodendrogenesis, neurogenesis, and axonal outgrowth. We, therefore, investigated whether the miR-17-92 cluster-enriched exosomes harvested from MSCs transfected with an miR-17-92 cluster plasmid enhance neurological recovery compared with control MSC-derived exosomes.Rats subjected to 2 hours of transient middle cerebral artery occlusion were intravenously administered miR-17-92 cluster-enriched exosomes, control MSC exosomes, or liposomes and were euthanized 28 days post-middle cerebral artery occlusion. Histochemistry, immunohistochemistry, and Golgi-Cox staining were used to assess dendritic, axonal, synaptic, and myelin remodeling. Expression of phosphatase and tensin homolog and activation of its downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3? in the peri-infarct region were measured by means of Western blots.Compared with the liposome treatment, both exosome treatment groups exhibited significant improvement of functional recovery, but miR-17-92 cluster-enriched exosome treatment had significantly more robust effects on improvement of neurological function and enhancements of oligodendrogenesis, neurogenesis, and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone (IBZ) than the control MSC exosome treatment. Moreover, miR-17-92 cluster-enriched exosome treatment substantially inhibited phosphatase and tensin homolog, a validated miR-17-92 cluster target gene, and subsequently increased the phosphorylation of phosphatase and tensin homolog downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3? compared with control MSC exosome treatment.Our data suggest that treatment of stroke with tailored exosomes enriched with the miR-17-92 cluster increases neural plasticity and functional recovery after stroke, possibly via targeting phosphatase and tensin homolog to activate the PI3K/protein kinase B/mechanistic target of rapamycin/glycogen synthase kinase 3? signaling pathway.

Dataset Information

The miR-17-92 microRNA cluster regulates multiple components of the TGF-? pathway in neuroblastoma.

Publications

The miR-17-92 microRNA cluster regulates multiple components of the TGF-β pathway in neuroblastoma.

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