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Bioinformatics analysis of high-throughput data to validate potential novel biomarkers and small molecule drugs for glioblastoma multiforme.

ABSTRACT: OBJECTIVE:There have been no recent improvements in the glioblastoma multiforme (GBM) outcome, with median survival remaining 15 months. Consequently, the need to identify novel biomarkers for GBM diagnosis and prognosis, and to develop targeted therapies is high. This study aimed to establish biomarkers for GBM pathogenesis and prognosis. METHODS:In total, 220 overlapping differentially expressed genes (DEGs) were obtained by integrating four microarray datasets from the Gene Expression Omnibus database (GSE4290, GSE12657, GSE15824, and GSE68848). Then a 140-node protein-protein interaction network with 343 interactions was constructed. RESULTS:The immune response and cell adhesion molecules were the most significantly enriched functions and pathways, respectively, among DEGs. The designated hub genes ITGB5 and RGS4, which have a high degree of connectivity, were closely correlated with patient prognosis, and GEPIA database mining further confirmed their differential expression in GBM versus normal tissue. We also determined the 20 most appropriate small molecules that could potentially reverse GBM gene expression, Prestwick-1080 was the most promising and had the highest negative scores. CONCLUSIONS:This study identified ITGB5 and RGS4 as potential biomarkers for GBM diagnosis and prognosis. Insights into molecular mechanisms governing GBM occurrence and progression will help identify alternative biomarkers for clinical practice.

SUBMITTER: Qi F

PROVIDER: S-EPMC7343367 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Bioinformatics analysis of high-throughput data to validate potential novel biomarkers and small molecule drugs for glioblastoma multiforme.

Qi Fuwei F Li Qing Q Lu Xiaojun X Chen Zhihua Z

The Journal of international medical research 20200701 7

<h4>Objective</h4>There have been no recent improvements in the glioblastoma multiforme (GBM) outcome, with median survival remaining 15 months. Consequently, the need to identify novel biomarkers for GBM diagnosis and prognosis, and to develop targeted therapies is high. This study aimed to establish biomarkers for GBM pathogenesis and prognosis.<h4>Methods</h4>In total, 220 overlapping differentially expressed genes (DEGs) were obtained by integrating four microarray datasets from the Gene Exp ...[more]

PMID: 32634050

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Project description:Background and aims:Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM and provide new diagnostic and therapies for GBM. Methods:Three microarray datasets (GSE111260, GSE103227, and GSE104267) were selected from Gene Expression Omnibus (GEO) database for integrated analysis. The differential expressed genes (DEGs) between GBM and normal tissues were identified. Then, prognosis-related DEGs were screened by survival analysis, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to explore the hub genes associated with GBM. The mRNA and protein expression levels of hub genes were respectively validated in silico using The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases. Subsequently, the small molecule drugs of GBM were predicted by using Connectivity Map (CMAP) database. Results:A total of 78 prognosis-related DEGs were identified, of which10 hub genes with higher degree were obtained by PPI analysis. The mRNA expression and protein expression levels of CETN2, MKI67, ARL13B, and SETDB1 were overexpressed in GBM tissues, while the expression levels of CALN1, ELAVL3, ADCY3, SYN2, SLC12A5, and SOD1 were down-regulated in GBM tissues. Additionally, these genes were significantly associated with the prognosis of GBM. We eventually predicted the 10 most vital small molecule drugs, which potentially imitate or reverse GBM carcinogenic status. Cycloserine and 11-deoxy-16,16-dimethylprostaglandin E2 might be considered as potential therapeutic drugs of GBM. Conclusions:Our study provided 10 key genes for diagnosis, prognosis, and therapy for GBM. These findings might contribute to a better comprehension of molecular mechanisms of GBM development, and provide new perspective for further GBM research. However, specific regulatory mechanism of these genes needed further elaboration.

Project description:ObjectiveTo explore the autophagy-related prognostic signature (ARPs) via data mining in gene expression profiles for glioblastoma (GBM).MethodsUsing the Cancer Genome Atlas (TCGA) database, we obtained 156 GBM samples and 5 adjacent normal samples, and denoted them as discovery cohort. Univariate Cox regression analysis was used to screen autophagy genes that related to GBM prognosis. Then, the least absolute shrinkage and selection operator Cox regression model was used to construct an autophagy-based ARPs, which was validated in an external cohort containing 80 GBM samples. The patients in the above-mentioned cohorts were divided into low-risk group and high-risk group according to the median prognostic risk score, and the diagnostic performance of the model was assessed by receiver operating characteristic curve analyses. The gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed between the high-risk and low-risk patients. Additionally, the genetic features of ARPs, such as genetic variation profiles, correlations with tumor-infiltrating lymphocytes (TILs), and potential drug sensitivity, were further assessed in the TCGA-GBM data set.ResultsA signature of ARPs including NDUFB9, BAK1, SUPT3H, GAPDH, CDKN1B, CHMP6, and EGFR were detected and validated. We identified a autophagy-related prognosis 7-gene signature correlated survival prognosis, immune infiltration, level of cytokines, and cytokine receptor in tumor microenvironment. Furthermore, the signature was tested in several pathways related to disorders of tumor microenvironment, as well as cancer-related pathways. Additionally, a range of small molecular drugs, shown to have a potential therapeutic effect on GBM.ConclusionsWe constructed an autophagy-based 7-gene signature, which could serve as an independent prognostic indicator for cases of GBM and sheds light on the role of autophagy as a potential therapeutic target in GBM.

Dataset Information

Bioinformatics analysis of high-throughput data to validate potential novel biomarkers and small molecule drugs for glioblastoma multiforme.

Publications

Bioinformatics analysis of high-throughput data to validate potential novel biomarkers and small molecule drugs for glioblastoma multiforme.

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