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

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.

Machine learning and statistical analysis to identify determinants of survival in primary glioblastoma using genome wide expression studies

“…Next, we identified master regulators which regulate activity of these TFs. Out of them, 4 master regulators, namely; IGFBP2, PDGFA, AEBP1, OSMR were reported to drive poor prognosis in GBM in our earlier published work [7]. Here, we report POSTN, CD14, CD44, DUSP6, FGFR3, GRB10 and IL1RAP to be playing critical roles in driving poor survival in GBM.…”

“…Using the DNA methylation patterns a new prediction tool is developed for 10 CpGs. These 10CpGs are superior to other molecular markers because they reflect the relationship between the GBM subtypes [Kloosterhof et al, 2013, Paul et al, 2017, Yin et al, 2018.…”

“…Decreased expression of the CHI3L1, FBLN4, EMP3, IGFBP2, IGFBP3, LGALS3, MAOB, PDPN, SERPING1 and TIMP1 genes have been reported to be associated with prolonged survival [3][4][5][6] based on gene expression analysis of extreme survivor groups (STS & LTS). In our earlier work we reported ~200 genes differentially expressed between 113 STS and 58 LTS using publicly available datasets [7]. However, in that analysis we have excluded the MTS group which forms a majority of the patient population.…”

“…IGFBP2 is considered as one of the strongest biomarkers of aggressive behavior in GBM [29,30] and also a prognostic marker for survival [30,31]. IGFBP2 along with AEBP1 (ACLP), PDGFA and OSMR are reported to be master regulators driving short survival in GBM and are discussed in detail in our earlier work [7].…”

“…Network is constructed using master regulators which have significant log2FC > 0.5. OSMR is included to validate the previously reported drivers of short-survival [7]. Three additional master-regulators (APEX1, MAPK8, PTK2B) as known drug targets are also added to the diagram.…”