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MicroRNA-182-5p targets a network of genes involved in DNA repair

ABSTRACT: MicroRNAs are non-coding regulators of gene expression, which act by repressing protein translation and/or degrading mRNA. Many have been shown to drive tumorigenesis in cancer, but functional studies to understand their mode of action are typically limited to single target genes. In this study we use synthetic biotinylated miRNA to pull down endogenous targets of miR-182. We identified over 1000 genes as potential targets of miR-182, most of which have a known function in pathways underlying tumour biology. Specifically, functional enrichment analysis identified components of both the DNA damage response pathway and cell cycle to be highly represented in this target cohort. Experimental validation confirmed that miR-182 mediated disruption of the homologous recombination (HR) pathway is a consequence of its ability to target multiple components in that pathway. Although there is a strong enrichment for the cell cycle ontology, we do not see a direct biological effect as a consequence of miR-182 over expression. We highlight targets which could be responsible for miR-182 mediated disruption of other biological processes attributed in the literature so far. Finally we show that miR-182 is highly expressed in a panel of human breast cancer samples highlighting its role as a potential oncomir in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38593 | GEO | 2013/01/29

SECONDARY ACCESSION(S): PRJNA168201

REPOSITORIES: GEO

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MicroRNA-182-5p targets a network of genes involved in DNA repair

Project description:MicroRNAs are non-coding regulators of gene expression, which act by repressing protein translation and/or degrading mRNA. Many have been shown to drive tumorigenesis in cancer, but functional studies to understand their mode of action are typically limited to single target genes. In this study we use synthetic biotinylated miRNA to pull down endogenous targets of miR-182. We identified over 1000 genes as potential targets of miR-182, most of which have a known function in pathways underlying tumour biology. Specifically, functional enrichment analysis identified components of both the DNA damage response pathway and cell cycle to be highly represented in this target cohort. Experimental validation confirmed that miR-182 mediated disruption of the homologous recombination (HR) pathway is a consequence of its ability to target multiple components in that pathway. Although there is a strong enrichment for the cell cycle ontology, we do not see a direct biological effect as a consequence of miR-182 over expression. We highlight targets which could be responsible for miR-182 mediated disruption of other biological processes attributed in the literature so far. Finally we show that miR-182 is highly expressed in a panel of human breast cancer samples highlighting its role as a potential oncomir in breast cancer. HEK293T cells were transfected with biotinylated miR-182 or a mock control. The miRNAs and target mRNA were pulled down with streptavidin and compared to the control.

2013-01-29 | E-GEOD-38593 | biostudies-arrayexpress

Identification of genes and molecular pathways associated with anti-miR-182 treatment.

Project description:To identify genes differentially modulated by anti-miR-182 treatment in a liver melanoma metastasis mouse model. Targeting oncogenic microRNAs is emerging as a promising strategy for cancer therapy. Here we provide proof-of-principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the effect of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, whose silencing represses invasion and induces apoptosis in vitro. In particular, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2â sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had an appreciably lower burden of liver metastases compared to the control. We confirmed that miR-182 levels were effectively downregulated in the anti-miR treated tumors relative to the scrambled treated tumor both in the liver and in the spleen. This downregulation was accompanied by an upregulation of miR-182 direct targets. Transcriptome analysis of mouse tissues treated with anti-miR-182 or scramble oligonucleotides revealed an enrichment for genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of target levels. Our results suggest that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide solid proof-of-principle for similar strategies against other metastatic tumors. Keywords: Differentially expressed genes (mRNAs) in response to miRNA inhibition Quadruplicate (n=4) samples of anti-miR-182 treated human melanoma metastasis compared to quadruplicate control treated metastasis.

2010-10-21 | E-GEOD-24824 | biostudies-arrayexpress

Identification of genes and molecular pathways associated with anti-miR-182 treatment.

Project description:To identify genes differentially modulated by anti-miR-182 treatment in a liver melanoma metastasis mouse model. Targeting oncogenic microRNAs is emerging as a promising strategy for cancer therapy. Here we provide proof-of-principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the effect of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, whose silencing represses invasion and induces apoptosis in vitro. In particular, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2’ sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had an appreciably lower burden of liver metastases compared to the control. We confirmed that miR-182 levels were effectively downregulated in the anti-miR treated tumors relative to the scrambled treated tumor both in the liver and in the spleen. This downregulation was accompanied by an upregulation of miR-182 direct targets. Transcriptome analysis of mouse tissues treated with anti-miR-182 or scramble oligonucleotides revealed an enrichment for genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of target levels. Our results suggest that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide solid proof-of-principle for similar strategies against other metastatic tumors. Keywords: Differentially expressed genes (mRNAs) in response to miRNA inhibition

2010-10-21 | GSE24824 | GEO

miR-182 induced gene expression alteration in glioma cells

Project description:This experiment is designed to evaluate gene expression alteration following miR-182 transfection in glioma cells. We find a significant elevation of NF kappa B transcriptional targets. Total RNA were extracted from SNB-19 glioma cells transfected with miR-182 mimic oligo or miRNA mimic negative control 36 hours after transfection, two biological replications for each treatment.

2011-11-15 | E-GEOD-33293 | biostudies-arrayexpress

miR-182 induced gene expression alteration in glioma cells

2011-11-15 | GSE33293 | GEO

Bone protection by inhibition of microRNA-182

Project description:We performed RNA-seq experiments, one with the WT control and Mir182ΔM/ΔM osteoclast precursors at baseline and after RANKL stimulation, the other with miR-182 gain of function approach using the control and Mir182mTg BMMs, to identify genes regulated by miR-182 in osteoclast precursors.

2018-09-04 | GSE108721 | GEO

miR-182 inhibition in AKI

Project description:gene expression modification after miR-182 inhibition, day 2 and day 7 after ischemic reperfusion injury

2017-06-30 | GSE69803 | GEO

miR-182-5p Promotes Hepatocyte-Stellate Cell Crosstalk to Facilitate Liver Regeneration

Project description:A unique feature of the liver is its high regenerative capacity, which is essential to maintain liver homeostasis. However, key regulators of liver regeneration (LR) remain ill-defined. Here, we identify hepatic miR-182-5p as a key regulator of LR. Suppressing miR-182-5p, whose expression is significantly induced in the liver of mice post two-thirds partial hepatectomy (PH), abrogates PH-induced LR in mice. In contrast, liver-specific overexpression of miR-182-5p promotes LR in mice with PH. Overexpression of miR-182-5p failed to promote proliferation in hepatocytes, but stimulates proliferation when hepatocytes are cocultured with stellate cells. Mechanistically, miR-182-5p stimulates Cyp7a1-mediated cholic acid production in hepatocytes, which promotes hedgehog (Hh) ligand production in stellate cells, leading to the activation of Hh signaling in hepatocytes and consequent cell proliferation. Collectively, our study identified miR-182-5p as a critical regulator of LR and uncovers a Cyp7a1/cholic acid-dependent mechanism by which hepatocytes crosstalk to stellate cells to facilitate LR.

2022-08-10 | GSE206451 | GEO

MiR-182 and miR-203 induce EMT

Project description:Expression profiling of prostate EPT1 cells transducted with two types of miRNAs (miR-182, miR-203) and RNAi clones knocking down SNAI2.

2012-04-27 | E-MTAB-1107 | biostudies-arrayexpress

The microRNA cluster miR-183/96/182 contributes to long-term memory in a protein phosphatase 1 dependent manner

Project description:Memory formation is a complex cognitive function regulated by coordinated synaptic and nuclear processes in neurons. In mammals, it is controlled by multiple molecular activators and suppressors, including the key signaling regulator protein phosphatase 1 (PP1). Here, we show that memory control by PP1 involves the miR-183/96/182 cluster, which is selectively regulated during memory formation. Inhibiting nuclear PP1 in mice brain or training in object recognition task similarly increases miR-183/96/182 expression in the hippocampus. Mimicking this increase by overexpressing miR-183/96/182 enhances object memory, while suppressing endogenous level of the cluster reduces it. This effect involves the modulation of many plasticity-related genes, and we identified HDAC9 as one of the functional targets. Further, PP1 controls miR-183/96/182 in a transcription-independent manner influencing processing of their precursors. These findings provide novel evidence for the role of miRNAs in memory formation and suggest the implication of PP1 in miRNAs processing in the adult brain.

2016-09-20 | GSE83707 | GEO

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