Identification of a miRNA multi-targeting therapeutic strategy in glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE246708 | GEO | 2023/11/03
REPOSITORIES: GEO
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Project description:Brain tumor neurospheres (BTCSs) are cancer cells with neural stem cell-like properties found in the fatal brain tumor glioblastoma multiforme (GBM). These cells account for less than 1% of total tumor cells, are poorly differentiated and are believed to be involved in tumor induction, progression, treatment resistance and relapse. Specific miRNAs play important roles in modulating the proliferation and differentiation of neural stem cells, therefore, we aimed to identify miRNAs controlling differentiation in GBM-BTSCs through high throughput screening miRNA array profiling. We compared the miRNA expression profiles at the neurosphere state and upon 4 and 14 days of differentiation by using LIMMA, finding 21 differentially expressed miRNAs : hsa-miR-103, hsa-miR-106a, hsa-miR-106b, hsa-miR-15b, hsa-miR-17, hsa-miR-19a, hsa-miR-20a, hsa-miR-25, hsa-miR-301a and hsa-miR-93 were found up-regulated upon differentiation, while hsa-miR-100, hsa-miR-1259, hsa-miR-21, hsa-miR-22, hsa-miR-221, hsa-miR-222, hsa-miR-23b, hsa-miR-27a, hsa-miR-27b, hsa-miR-29a and hsa-miR-29b were down-regulated. Expression of 11 of the 21 miRNAs was examined by qPCR and 7 of them were validated: hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222 increased their expression upon differentiation, while hsa-miR-93 and hsa-miR-106a were inhibited. Functional studies demonstrated that miR-21 over-expression induced the expression of glial and/or neuronal cell markers in the neurospheres, possibly due to SPRY1 targeting by miR-21 in these cells, while miR-221 and miR-222 inhibition at the differentiated state reduced the expression of those differentiation markers. On the other hand, miR-29a and miR-29b targeted MCL1 in the GBM neurospheres and increased apoptotic cell death. Five GBM cell lines at the neurosphere state or after 4 or 14 days of differentiation
2013-03-05 | E-GEOD-44842 | biostudies-arrayexpress
Project description:Brain tumor neurospheres (BTCSs) are cancer cells with neural stem cell-like properties found in the fatal brain tumor glioblastoma multiforme (GBM). These cells account for less than 1% of total tumor cells, are poorly differentiated and are believed to be involved in tumor induction, progression, treatment resistance and relapse. Specific miRNAs play important roles in modulating the proliferation and differentiation of neural stem cells, therefore, we aimed to identify miRNAs controlling differentiation in GBM-BTSCs through high throughput screening miRNA array profiling. We compared the miRNA expression profiles at the neurosphere state and upon 4 and 14days of differentiation by using LIMMA, finding 21 differentially expressed miRNAs : hsa-miR-103, hsa-miR-106a, hsa-miR-106b, hsa-miR-15b, hsa-miR-17, hsa-miR-19a, hsa-miR-20a, hsa-miR-25, hsa-miR-301a and hsa-miR-93 were found up-regulated upon differentiation, while hsa-miR-100, hsa-miR-1259, hsa-miR-21, hsa-miR-22, hsa-miR-221, hsa-miR-222, hsa-miR-23b, hsa-miR-27a, hsa-miR-27b, hsa-miR-29a and hsa-miR-29b were down-regulated. Expression of 11 of the 21 miRNAs was examined by qPCR and 7 of them were validated: hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222 increased their expression upon differentiation, while hsa-miR-93 and hsa-miR-106a were inhibited. Functional studies demonstrated that miR-21 over-expression induced the expression of glial and/or neuronal cell markers in the neurospheres, possibly due to SPRY1 targeting by miR-21 in these cells, while miR-221 and miR-222 inhibition at the differentiated state reduced the expression of those differentiation markers. On the other hand, miR-29a and miR-29b targeted MCL1 in the GBM neurospheres and increased apoptotic cell death. Gene expression in differentiated cells relative to neurospheres in four different glioblastoma cultures
2013-03-05 | E-GEOD-44841 | biostudies-arrayexpress
Project description:Brain tumor neurospheres (BTCSs) are cancer cells with neural stem cell-like properties found in the fatal brain tumor glioblastoma multiforme (GBM). These cells account for less than 1% of total tumor cells, are poorly differentiated and are believed to be involved in tumor induction, progression, treatment resistance and relapse. Specific miRNAs play important roles in modulating the proliferation and differentiation of neural stem cells, therefore, we aimed to identify miRNAs controlling differentiation in GBM-BTSCs through high throughput screening miRNA array profiling. We compared the miRNA expression profiles at the neurosphere state and upon 4 and 14days of differentiation by using LIMMA, finding 21 differentially expressed miRNAs : hsa-miR-103, hsa-miR-106a, hsa-miR-106b, hsa-miR-15b, hsa-miR-17, hsa-miR-19a, hsa-miR-20a, hsa-miR-25, hsa-miR-301a and hsa-miR-93 were found up-regulated upon differentiation, while hsa-miR-100, hsa-miR-1259, hsa-miR-21, hsa-miR-22, hsa-miR-221, hsa-miR-222, hsa-miR-23b, hsa-miR-27a, hsa-miR-27b, hsa-miR-29a and hsa-miR-29b were down-regulated. Expression of 11 of the 21 miRNAs was examined by qPCR and 7 of them were validated: hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222 increased their expression upon differentiation, while hsa-miR-93 and hsa-miR-106a were inhibited. Functional studies demonstrated that miR-21 over-expression induced the expression of glial and/or neuronal cell markers in the neurospheres, possibly due to SPRY1 targeting by miR-21 in these cells, while miR-221 and miR-222 inhibition at the differentiated state reduced the expression of those differentiation markers. On the other hand, miR-29a and miR-29b targeted MCL1 in the GBM neurospheres and increased apoptotic cell death.
2013-03-05 | GSE44841 | GEO
Project description:Brain tumor neurospheres (BTCSs) are cancer cells with neural stem cell-like properties found in the fatal brain tumor glioblastoma multiforme (GBM). These cells account for less than 1% of total tumor cells, are poorly differentiated and are believed to be involved in tumor induction, progression, treatment resistance and relapse. Specific miRNAs play important roles in modulating the proliferation and differentiation of neural stem cells, therefore, we aimed to identify miRNAs controlling differentiation in GBM-BTSCs through high throughput screening miRNA array profiling. We compared the miRNA expression profiles at the neurosphere state and upon 4 and 14 days of differentiation by using LIMMA, finding 21 differentially expressed miRNAs : hsa-miR-103, hsa-miR-106a, hsa-miR-106b, hsa-miR-15b, hsa-miR-17, hsa-miR-19a, hsa-miR-20a, hsa-miR-25, hsa-miR-301a and hsa-miR-93 were found up-regulated upon differentiation, while hsa-miR-100, hsa-miR-1259, hsa-miR-21, hsa-miR-22, hsa-miR-221, hsa-miR-222, hsa-miR-23b, hsa-miR-27a, hsa-miR-27b, hsa-miR-29a and hsa-miR-29b were down-regulated. Expression of 11 of the 21 miRNAs was examined by qPCR and 7 of them were validated: hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222 increased their expression upon differentiation, while hsa-miR-93 and hsa-miR-106a were inhibited. Functional studies demonstrated that miR-21 over-expression induced the expression of glial and/or neuronal cell markers in the neurospheres, possibly due to SPRY1 targeting by miR-21 in these cells, while miR-221 and miR-222 inhibition at the differentiated state reduced the expression of those differentiation markers. On the other hand, miR-29a and miR-29b targeted MCL1 in the GBM neurospheres and increased apoptotic cell death.
2013-03-05 | GSE44842 | GEO
Project description:Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM. Methods.Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS). Results. At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months). Conclusions. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
2020-12-31 | GSE154042 | GEO
Project description:Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM. Methods.Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS). Results. At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months). Conclusions. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
2020-12-31 | GSE154041 | GEO
Project description:Hepatocellular carcinoma (HCC) is one of the most common causes of death worldwide and the fourth most prevalent type of cancer. Whereas curative treatments such as liver transplantation, ablation or surgery are optimal for early stages, only paliative treatments are given to intermediate and advanced stages of the disease. Despite the introduction of immune regulators as first-line treatments for advanced stages, Sorafenib is still the standard of care in the clinical practice. In cell lysates, anti-tumoral properties of Sorafenib were related to upregulation of miR-200c-3p (anti-tumoral miRNA) at 6 hours of treatment and downregulation of miR-222-5p and miR-512-3p (pro-tumoral miRNAs) at 24 hours. We have identified these miRNA biomarkers of Sorafenib treatment response in plasma of patients with advanced HCC treated with Sorafenib. In particular, miR-200c-3p has been related to increased survival benefit whereas miR-222-5p and miR-512-3p have been related to worse prognosis. Our study has sequenced HepG2 cells treated with Sorafenib and miR-200c-3p inhibitor, and transfected with miR-222-5p and miR-512-3p mimics to unravel the molecular pathways governing Sorafenib response
2022-04-28 | GSE201695 | GEO
Project description:Microglia were derived from iPSCs and treated with mimics and inhibitors of the miRNAs hsa-miR-150-5p, hsa-miR-193a-3p and hsa-miR-19b-3p. RNA-sequencing was then performed to examine the effects of up- and down-regulation of the respective miRNAs.
| EGAD00001006842 | EGA
Project description:Background: Oral squamous cell carcinoma (OSCC) is often diagnosed at a late stage and may be malignantly transformed from oral leukoplakia (OL). This study aimed to identify potential plasma microRNAs (miRNAs) for the early detection of oral cancer. Methods: Plasma from normal, OL, and OSCC patients were evaluated. Small RNA sequencing was used to screen differently expressed miRNAs among the groups. Next, these miRNAs were validated with individual samples by quantitative real-time polymerase chain reaction (qRT-PCR) assays. The possible physiological roles of the identified miRNAs were further investigated using bioinformatics analysis. Results: Three miRNAs (miR-222-3p, miR-150-5p, and miR-423-5p) were identified as differentially expressed among groups; miR-222-3p and miR-423-5p negatively correlated with T stage, lymph node metastasis status, and clinical stage. A high diagnostic accuracy (Area under curve = 0.88) was demonstrated for discriminating OL from OSCC. Bioinformatics analysis reveals that miR-423-5p and miR-222-3p are significantly over-expressed in oral cancer tissues and involved in various cancer pathways. Conclusions: The three plasma miRNA panel may be useful to monitor malignant progression from OL to OSCC and as potential biomarkers for early detection of oral cancer.
2018-04-17 | GSE104440 | GEO
Project description:Background: Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterise extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.Methods: Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterisation was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analysed by high-resolution mass spectrometry.Results: We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR- 323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.Conclusion: Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.
2024-04-09 | PXD047328 | Pride