Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126073 | GEO | 2019/09/30
REPOSITORIES: GEO
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Project description:Method: Analysis of the transcriptomal changes in wildtype mouse glioma tumor cells compared to miR-21 knockout glioma tumor cells (GL261) Result: transcriptional changes are driven through miR-21
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Project description:Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21
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Project description:MiR-21 is an important suppressor of T-cell apoptosis that is also widely overexpressed in many types of cancers. The exact mechanisms related to the anti-apoptotic effect of miR-21 is not well understood. In this study, we applied AGO2 RNA Immunoprecipitation followed by gene expression profiling (RIP-Chip) in Jurkat cells to identify apoptosis-associated miR-21 target genes. We showed that expression of miR-21 rapidly increases upon αCD3/αCD28 activation of Jurkat cells. Inhibition of miR-21 resulted in reduced cell growth and induced apoptosis. Upon AGO2-RIP-Chip, we observed an overall increased enrichment of miR-21 target genes in the IP fraction of miR-21-overexpressing Jurkat cells as compared to the IP fraction of empty vector control cells. We noted a systematic decrease in transcript levels of predicted miR-21 target genes compared to EV control. We identified 72 genes that were 2-fold enriched in the AGO2-IP fraction of miR-21-overexpressing cells that contained a predicted miR-21 binding site. Of these, 71 were enriched 2-fold more in the miR-21-overexpressing cells as compared to EV Jurkat cells. The target gene for which the enrichment was most prominently increased upon miR-21 overexpression was the pro-apoptotic protein LATS1. Luciferase reporter assays confirmed direct targeting of the LATS1 3'UTR by miR-21. In line with the luciferase results, Western blot analysis revealed a decrease in LATS1 upon miR-21 inhibition. LATS1 qRT-PCR analysis in primary T-cells showed that LATS1 levels decrease upon T-cell stimulation while the miR-21 levels increase. Collectively, these data identify the miR-21 target LATS1 as a likely candidate whose inhibition contributes to the anti-apoptotic function of miR-21 in T-cells and perhaps also many types of cancers. Gene expression array on Jurkat cells overexpressing miR-21 and empty vector (EV).
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Project description:Intercellular communication orchestrates effective immune responses against disease-causing agents. Extracellular vesicles (EVs) are potent mediators of cell-cell communication. EVs carry bioactive molecules, including microRNAs, which modulate gene expression and function in the recipient cell. Here, we show that formation of cognate primary T-B lymphocyte immune contacts promotes transfer to the B cell of a very restricted set of T cell EV-microRNAs (mmu-miR20a-5p, mmu-miR-25-3p and mmu-miR-155-3p). Transferred EV-microRNAs target key genes that control B cell function, including the pro-apoptotic BIM and the cell-cycle regulator PTEN. EV-microRNAs transferred in T-B cognate interactions also promote survival, proliferation and antibody class switching. Using mouse chimeras with Rab27KO EV-deficient T cells, we demonstrate that small EV transfer is required for the germinal center reaction and antibody production in vivo, revealing a novel mechanism that controls B cell responses through the transfer of EV-microRNAs of T cell origin. These findings provide mechanistic insight on the Griscelli syndrome, associated with a mutation in the Rab27a gene and may shed light on this pathogenesis and other immune-related and inflammatory disorders. This SuperSeries is composed of the SubSeries listed below.
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Project description:MiR-21 is an important suppressor of T-cell apoptosis that is also widely overexpressed in many types of cancers. The exact mechanisms related to the anti-apoptotic effect of miR-21 is not well understood. In this study, we applied AGO2 RNA Immunoprecipitation followed by gene expression profiling (RIP-Chip) in Jurkat cells to identify apoptosis-associated miR-21 target genes. We showed that expression of miR-21 rapidly increases upon αCD3/αCD28 activation of Jurkat cells. Inhibition of miR-21 resulted in reduced cell growth and induced apoptosis. Upon AGO2-RIP-Chip, we observed an overall increased enrichment of miR-21 target genes in the IP fraction of miR-21-overexpressing Jurkat cells as compared to the IP fraction of empty vector control cells. We noted a systematic decrease in transcript levels of predicted miR-21 target genes compared to EV control. We identified 72 genes that were 2-fold enriched in the AGO2-IP fraction of miR-21-overexpressing cells that contained a predicted miR-21 binding site. Of these, 71 were enriched 2-fold more in the miR-21-overexpressing cells as compared to EV Jurkat cells. The target gene for which the enrichment was most prominently increased upon miR-21 overexpression was the pro-apoptotic protein LATS1. Luciferase reporter assays confirmed direct targeting of the LATS1 3'UTR by miR-21. In line with the luciferase results, Western blot analysis revealed a decrease in LATS1 upon miR-21 inhibition. LATS1 qRT-PCR analysis in primary T-cells showed that LATS1 levels decrease upon T-cell stimulation while the miR-21 levels increase. Collectively, these data identify the miR-21 target LATS1 as a likely candidate whose inhibition contributes to the anti-apoptotic function of miR-21 in T-cells and perhaps also many types of cancers.
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Project description:Murine BV2 microglia cells were transfected either with siRNA negative control or siRNA against caspase-3 for 48h. Later on some the of the BV2 transfected cells were co-cultured with C6 glioma cells during 6h. We used the SA Biosciences Mouse Wound Healing PCR Array (PAMM-121Z) to quantitate gene expression of relevant genes related to the wound healing process Glioma cells recruit and exploit microglia, resident immune cells of the brain, for their proliferation and invasion capability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype remains elusive. Here, we report that glioma-induced microglia conversion is coupled to a reduction of basal microglial caspase-3 activity, increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and demonstrate that caspase-3 inhibition regulates microglial tumor-supporting function. Further, we identified nitric oxide synthase-2 (NOS2) activity originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to reduction in both microglia recruitment and tumor expansion, whereas depletion of the microglial caspase-3 gene promoted tumor growth. This study provides evidence that the inhibition of Trx2-mediated denitrosylation of SNO-procaspase-3 is part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells. qPCR gene expression profiling. Three independent experiments of siControl BV2 monoculture, siCaspase3 BV2 monoculture, siControl BV2 cocultured 6h with C6 glioma cells and siCaspase3 BV2 cocultured 6h with C6 glioma cells. Equal amount total RNA from each culture was used for the gene expression analysis. Please note that the raw data for three independent experiments (prior to averaging the data) is provided in the 'Raw_Data_File_with_the_Ct_values_for_3_indep_experiments.txt'.
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Project description:Gene-editing of miR-21 to target glioma
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Project description:MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Here, we identified microglia as the main cellular source of miR-146a among mouse CNS resident cells. We further characterized the phenotype of miR-146a KO microglia cells during in vivo demyelination induced by cuprizone (CPZ) and found reduced number of CD11c+ microglia in the KO compared to WT mice. Microglia were also isolated from the brain, and the proteome was analyzed by liquid chromatography mass spectrometry.
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