Identification of Hub Genes and Key Pathways Associated with Anti-VEGF Resistant Glioblastoma Using Gene Expression Data Analysis.

Kesavan R Arya,Chandran S Abhinand,Oommen V Oommen,Perumana R Sudhakaran,Achuthsankar S Nair,Ramachandran P Bharath Chand

doi:10.3390/biom11030403

Abstract

Anti-VEGF therapy is considered to be a useful therapeutic approach in many tumors, but the low efficacy and drug resistance limit its therapeutic potential and promote tumor growth through alternative mechanisms. We reanalyzed the gene expression data of xenografts of tumors of bevacizumab-resistant glioblastoma multiforme (GBM) patients, using bioinformatics tools, to understand the molecular mechanisms of this resistance. An analysis of the gene set data from three generations of xenografts, identified as 646, 873 and 1220, differentially expressed genes (DEGs) in the first, fourth and ninth generations, respectively, of the anti-VEGF-resistant GBM cells. Gene Ontology (GO) and pathway enrichment analyses demonstrated that the DEGs were significantly enriched in biological processes such as angiogenesis, cell proliferation, cell migration, and apoptosis. The protein–protein interaction network and module analysis revealed 21 hub genes, which were enriched in cancer pathways, the cell cycle, the HIF1 signaling pathway, and microRNAs in cancer. The VEGF pathway analysis revealed nine upregulated (IL6, EGFR, VEGFA, SRC, CXCL8, PTGS2, IDH1, APP, and SQSTM1) and five downregulated hub genes (POLR2H, RPS3, UBA52, CCNB1, and UBE2C) linked with several of the VEGF signaling pathway components. The survival analysis showed that three upregulated hub genes (CXCL8, VEGFA, and IDH1) were associated with poor survival. The results predict that these hub genes associated with the GBM resistance to bevacizumab may be potential therapeutic targets or can be biomarkers of the anti-VEGF resistance of GBM.

Highlights

These results revealed that three hub genes with higher expression levels (VEGFA, CXCL8, and IDH1) were associated with a significantly shorter overall survival time among patients with glioblastoma multiforme (GBM) (log-rank p ≤ 0.05 and p(HR or hazard ratio) ≤ 0.05) (Figure 6A,B), suggesting that these hub genes are associated with the pathophysiology of bevacizumabresistant GBM
GBM, using bioinformatics tools, and the results from anti-VEGF-resistant GBM, using bioinformatics tools, and the results suggested that suggested that the cells adapt to such conditions by changing gene expression and rethe cells adapt to such conditions by changing gene expression and restoring angiogenesis
The results presented here predict that the hub genes associated with the GBM resistance to bevacizumab may be a potential therapeutic target or biomarker of anti-VEGF resistance of GBM

Summary

Introduction

The formation of new blood vessels from existing vessel in the postnatal life, referred to as angiogenesis, is an important process in both physiological and pathological conditions. It is a tightly regulated process involving the interplay of a number of pro- and antiangiogenic factors. Dysregulation of the balance between these factors leads to excess or inhibited angiogenesis, contributing to different pathological conditions [1,2,3]. Tumors cannot grow beyond a certain size unless they are vascularized to supply oxygen and much-needed nutrients for their growth.

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Conclusion