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MiR-592 activates the mTOR kinase, ERK1/ERK2 kinase signaling and imparts neuronal differentiation signature characteristic of Group 4 medulloblastoma

ABSTRACT: The expression of miR-592 was found to reduce the malignant potential of Group 3 medulloblastoma cell lines, D283, D425 and HD-MB03. RNA-seq analysis was carried out to identify genes differentially expressed upon miR-592 expression in the medulloblastoma cell lines. MiR-592 expression was found to upregulate mTOR and ERK1/ERK2 signaling and bring about neuronal differentiation in D283 and D425 cells. Transcriptome sequencing was also carried out on the RNA extracted from the polyclonal population of D283 and D425 expressing miR-592 as well as the vector control population cells treated with rapamycin or U0126, a MAPK inhibitor to study if the mTOR signaling or MAPK signaling is instrumental in bringing about the neuronal differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147145 | GEO | 2021/08/26

REPOSITORIES: GEO

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Project description:Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor. The aim of our study was to understand which mechanisms are involved in aberrant activation of Wnt pathway and its association with MB tumor development. We studied the expression profiles of 19 MBs tumors using a genome-wide approach, furthermore we have included the data obtained from four independent public Datasets of gene expression (see README file below) to increase the statistical power of the study. The expression profiles identified the Wnt inhibitor gene, DKK3, significant down-regulated. DKK3 down-regulation was confirmed by qPCR in 80% of samples (27/33 MB tumors and in 3/5 MB human cell lines). Since DKK3 was found methylated in several cancers we also investigated the status of methylated CpG sites within the three promoters by a combination of two approaches: the MSP and pyrosequencing. MSP showed no methylation in all promoters while the pyrosequencing, a quantitative technique, indicated a very low level of methylation. To verify the epigenetic involvement on DKK3 silencing, we also studied the effect of Trichostatin A (TSA) in 4 MB cell lines (DAOY; D283; D425; D458). After TSA treatment we observed a significant DKK3 mRNA expression increase in 3/4 cell lines compared to the no treated cells. DAOY cells, that have a normal DKK3 expression value, did not change significantly the DKK3 expression after TSA treatment. To further validate the role of histone tail modifications as an epigenetic silencing mechanism for DKK3 in MB, we performed Chromatin Immunoprecipitation (ChIP) experiment using antibodies against acetylated histones. According to our earlier results, TSA treatment increased the signal of the histone modification meH3K4 which is related to a transcriptionally active gene respect to the untreated controls. Finally, we evaluated the DKK3 protein in three MB cell lines (DAOY; D283; D425) after 24h of TSA treatment, by immunofluorescence. We analysed 19 Medulloblastoma tumor from pediatric patients, a commercial pool (Clontech) of 24 normal cerebellum from female and male Caucasians (ages: 16-70 years; cause of death: sudden death) and a pool of 10 normal cerebellum from children (6 Caucasians and 4 African Americans; ages: 0-16 years; cause of death: sudden death) using 44K whole genome oligonucleotids microarray

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MiR-592 activates the mTOR kinase, ERK1/ERK2 kinase signaling and imparts neuronal differentiation signature characteristic of Group 4 medulloblastoma

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