IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available data...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.670240/full |
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| author | Manasa Kalya Manasa Kalya Alexander Kel Alexander Kel Darius Wlochowitz Edgar Wingender Tim Beißbarth |
| author_facet | Manasa Kalya Manasa Kalya Alexander Kel Alexander Kel Darius Wlochowitz Edgar Wingender Tim Beißbarth |
| author_sort | Manasa Kalya |
| collection | DOAJ |
| description | Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated. |
| first_indexed | 2024-12-21T15:55:27Z |
| format | Article |
| id | doaj.art-e15590b99d0c4ea5a178a487e7a161cd |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-21T15:55:27Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-e15590b99d0c4ea5a178a487e7a161cd2022-12-21T18:58:07ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-06-011210.3389/fgene.2021.670240670240IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma MultiformeManasa Kalya0Manasa Kalya1Alexander Kel2Alexander Kel3Darius Wlochowitz4Edgar Wingender5Tim Beißbarth6Department of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, GermanygeneXplain GmbH, Wolfenbüttel, GermanygeneXplain GmbH, Wolfenbüttel, GermanyInstitute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, RussiaDepartment of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, GermanygeneXplain GmbH, Wolfenbüttel, GermanyDepartment of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, GermanyOnly 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated.https://www.frontiersin.org/articles/10.3389/fgene.2021.670240/fullglioblastomamaster regulatorsupstream analysisIGFBP2FRA-1FOSL1 |
| spellingShingle | Manasa Kalya Manasa Kalya Alexander Kel Alexander Kel Darius Wlochowitz Edgar Wingender Tim Beißbarth IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme Frontiers in Genetics glioblastoma master regulators upstream analysis IGFBP2 FRA-1 FOSL1 |
| title | IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme |
| title_full | IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme |
| title_fullStr | IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme |
| title_full_unstemmed | IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme |
| title_short | IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme |
| title_sort | igfbp2 is a potential master regulator driving the dysregulated gene network responsible for short survival in glioblastoma multiforme |
| topic | glioblastoma master regulators upstream analysis IGFBP2 FRA-1 FOSL1 |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.670240/full |
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