IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme.

Manasa Kalya,Alexander Kel,Edgar Wingender,Tim Beißbarth,Darius Wlochowitz

doi:10.3389/fgene.2021.670240

Abstract

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.

Highlights

Glioblastoma multiforme (GBM) is the most common, highly malignant primary brain tumor (Wen and Kesari, 2008)
This work focuses on understanding gene regulatory networks that drive short survival in GBM and their master regulators, which we suggest as biomarkers and therapeutic targets
The full list corresponding log2FC are shown in Table 1 and the full list is of enrichment results can be found in Supplementary Table 1-B. given in Supplementary Table 1-A

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common, highly malignant primary brain tumor (Wen and Kesari, 2008). 2% of patients respond to standard therapy and survive beyond 36 months (Krex et al, 2007; Das et al, 2011), clinically called long-term survivors (LTS). Another group termed short-term survivors (STS) are those who survive less than 12 months (Shinawi et al, 2013). A better characterization of these extreme survival groups at the molecular level will likely shed important light on the biological aspects that drive their malignancy and survival

Methods

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Discussion

Conclusion