Molecular mechanisms underlying gliomas and glioblastoma pathogenesis revealed by bioinformatics analysis of microarray data

Basavaraj Vastrad, Chanabasayya Vastrad, Ashok Godavarthi, Raghu Chandrashekar

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The aim of this study was to identify key genes associated with gliomas and glioblastoma and to explore the related signaling pathways. Gene expression profiles of three glioma stem cell line samples, three normal astrocyte samples, three astrocyte overexpressing 4 iPSC-inducing and oncogenic factors (myc(T58A), OCT-4, p53DD, and H-Ras(G12V)) samples, three astrocyte overexpressing 7 iPSC-inducing and oncogenic factors (OCT4, H-Ras(G12V), myc(T58A), p53DD, cyclin D1, CDK4(RC24) and hTERT) samples and three glioblastoma cell line samples were downloaded from the ArrayExpress database (accession: E-MTAB-4771). The differentially expressed genes (DEGs) in gliomas and glioblastoma were identified using FDR and t tests, and protein–protein interaction (PPI) networks for these DEGs were constructed using the protein interaction network analysis. The GeneTrail2 1.5 tool was used to identify potentially enriched biological processes among the DEGs using gene ontology (GO) terms and to identify the related pathways using the Kyoto Encyclopedia of Genes and Genomes, Reactome and WikiPathways pathway database. In addition, crucial modules of the constructed PPI networks were identified using the PEWCC1 plug-in, and their topological properties were analyzed using NetworkAnalyzer, both available from Cytoscape. We also constructed microRNA–target gene regulatory network and transcription factor–target gene regulatory network for these DEGs were constructed using the miRNet and binding and expression target analysis. We identified 200 genes that could potentially be involved in the gliomas and glioblastoma. Among them, bioinformatics analysis identified 137 up-regulated and 63 down-regulated DEGs in gliomas and glioblastoma. The significant enriched pathway (PI3K-Akt) for up-regulated genes such as COL4A1, COL4A2, EGFR, FGFR1, LAPR6, MYC, PDGFA, SPP1 were selected as well as significant GO term (ear development) for up-regulated genes such as CELSR1, CHRNA9, DDR1, FGFR1, GLI2, LGR5, SOX2, TSHR were selected, while the significant enriched pathway (amebiasis) for down-regulated gene such as COL3A1, COL5A2, LAMA2 were selected as well as significant GO term (RNA polymerase II core promoter proximal region sequence-specific binding (5) such as MEIS2, MEOX2, NR2E1, PITX2, TFAP2B, ZFPM2 were selected. Importantly, MYC and SOX2 were hub proteins in the up-regulated PPI network, while MET and CDKN2A were hub proteins in the down-regulated PPI network. After network module analysis, MYC, FGFR1 and HOXA10 were selected as the up-regulated coexpressed genes in the gliomas and glioblastoma, while SH3GL3 and SNRPN were selected as the down-regulated coexpressed genes in the gliomas and glioblastoma. MicroRNA hsa-mir-22-3p had a regulatory effect on the most up DEGs, including VSNL1, while hsa-mir-103a-3p had a regulatory effect on the most down DEGs, including DAPK1. Transcription factor EZH2 had a regulatory effect on the both up and down DEGs, including CD9, CHI3L1, MEIS2 and NR2E1. The DEGs, such as MYC, FGFR1, CDKN2A, HOXA10 and MET, may be used for targeted diagnosis and treatment of gliomas and glioblastoma.

Original languageEnglish
Article number182
JournalMedical Oncology
Volume34
Issue number11
DOIs
Publication statusPublished - 01-11-2017

Fingerprint

Glioblastoma
Microarray Analysis
Computational Biology
Glioma
Genes
Gene Ontology
Astrocytes
Gene Regulatory Networks
snRNP Core Proteins
Databases
Encyclopedias
Protein Interaction Maps
Biological Phenomena
Cell Line
Amebiasis
RNA Polymerase II
Cyclin D1
MicroRNAs
Phosphatidylinositol 3-Kinases
Transcriptome

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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title = "Molecular mechanisms underlying gliomas and glioblastoma pathogenesis revealed by bioinformatics analysis of microarray data",
abstract = "The aim of this study was to identify key genes associated with gliomas and glioblastoma and to explore the related signaling pathways. Gene expression profiles of three glioma stem cell line samples, three normal astrocyte samples, three astrocyte overexpressing 4 iPSC-inducing and oncogenic factors (myc(T58A), OCT-4, p53DD, and H-Ras(G12V)) samples, three astrocyte overexpressing 7 iPSC-inducing and oncogenic factors (OCT4, H-Ras(G12V), myc(T58A), p53DD, cyclin D1, CDK4(RC24) and hTERT) samples and three glioblastoma cell line samples were downloaded from the ArrayExpress database (accession: E-MTAB-4771). The differentially expressed genes (DEGs) in gliomas and glioblastoma were identified using FDR and t tests, and protein–protein interaction (PPI) networks for these DEGs were constructed using the protein interaction network analysis. The GeneTrail2 1.5 tool was used to identify potentially enriched biological processes among the DEGs using gene ontology (GO) terms and to identify the related pathways using the Kyoto Encyclopedia of Genes and Genomes, Reactome and WikiPathways pathway database. In addition, crucial modules of the constructed PPI networks were identified using the PEWCC1 plug-in, and their topological properties were analyzed using NetworkAnalyzer, both available from Cytoscape. We also constructed microRNA–target gene regulatory network and transcription factor–target gene regulatory network for these DEGs were constructed using the miRNet and binding and expression target analysis. We identified 200 genes that could potentially be involved in the gliomas and glioblastoma. Among them, bioinformatics analysis identified 137 up-regulated and 63 down-regulated DEGs in gliomas and glioblastoma. The significant enriched pathway (PI3K-Akt) for up-regulated genes such as COL4A1, COL4A2, EGFR, FGFR1, LAPR6, MYC, PDGFA, SPP1 were selected as well as significant GO term (ear development) for up-regulated genes such as CELSR1, CHRNA9, DDR1, FGFR1, GLI2, LGR5, SOX2, TSHR were selected, while the significant enriched pathway (amebiasis) for down-regulated gene such as COL3A1, COL5A2, LAMA2 were selected as well as significant GO term (RNA polymerase II core promoter proximal region sequence-specific binding (5) such as MEIS2, MEOX2, NR2E1, PITX2, TFAP2B, ZFPM2 were selected. Importantly, MYC and SOX2 were hub proteins in the up-regulated PPI network, while MET and CDKN2A were hub proteins in the down-regulated PPI network. After network module analysis, MYC, FGFR1 and HOXA10 were selected as the up-regulated coexpressed genes in the gliomas and glioblastoma, while SH3GL3 and SNRPN were selected as the down-regulated coexpressed genes in the gliomas and glioblastoma. MicroRNA hsa-mir-22-3p had a regulatory effect on the most up DEGs, including VSNL1, while hsa-mir-103a-3p had a regulatory effect on the most down DEGs, including DAPK1. Transcription factor EZH2 had a regulatory effect on the both up and down DEGs, including CD9, CHI3L1, MEIS2 and NR2E1. The DEGs, such as MYC, FGFR1, CDKN2A, HOXA10 and MET, may be used for targeted diagnosis and treatment of gliomas and glioblastoma.",
author = "Basavaraj Vastrad and Chanabasayya Vastrad and Ashok Godavarthi and Raghu Chandrashekar",
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Molecular mechanisms underlying gliomas and glioblastoma pathogenesis revealed by bioinformatics analysis of microarray data. / Vastrad, Basavaraj; Vastrad, Chanabasayya; Godavarthi, Ashok; Chandrashekar, Raghu.

In: Medical Oncology, Vol. 34, No. 11, 182, 01.11.2017.

Research output: Contribution to journalArticle

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