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High Gene Expression Levels of VEGFA and CXCL8 in the Peritumoral Brain Zone Are Associated with the Recurrence of Glioblastoma: a Bioinformatics Analysis

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ONCOLOGY LETTERS 18: 6171-6179, 2019 High gene expression levels of VEGFA and CXCL8 in the peritumoral brain zone are associated with the recurrence of glioblastoma: A bioinformatics analysis XIAOBIN LUO1, SHANGYI XU1, YALI ZHONG2, TIANQI TU1, YOULIN XU1, XIANGLONG LI1, BIN WANG1 and FUBING YANG1 1Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000; 2School of Nursing, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550000, P.R. China Received April 25, 2019; Accepted September 17, 2019 DOI: 10.3892/ol.2019.10988 Abstract. The present study aimed to identify differentially of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes regulated genes between the peritumoral brain zone (PBZ) and Genomes (KEGG) databases. The Search Tool for the and tumor core (TC) of glioblastoma (GBM), to elucidate the Retrieval of Interacting Genes/Proteins online tool was used underlying molecular mechanisms and provide a target for the to construct a protein-protein interaction (PPI) network of treatment of tumors. The GSE13276 and GSE116520 data- DEGs. Hub genes were identified using Cytohubba, a plug‑in sets were downloaded from the Gene Expression Omnibus for Cytoscape. The Gene Expression Profiling Interactive (GEO) database. Differentially expressed genes (DEGs) for Analysis (GEPIA) database was utilized to perform survival the PBZ and TC were obtained using the GEO2R tool. The analysis. In total, 75 DEGs, including 12 upregulated and bioinformatics and evolutionary genomics online tool Venn 63 downregulated genes, were identified. In the GO term was used to identify common DEGs between the two datasets. analysis, these DEGs were mainly enriched in ‘regulation The Database for Annotation, Visualization, and Integrated of angiogenesis’ and ‘central nervous system development’. Discovery online tool was used to analyze enriched pathways Furthermore, in the KEGG pathway analysis, the DEGs were mainly enriched in ‘bladder cancer’ and ‘endocytosis’. When filtering the results of the PPI network analysis using Cytohubba, a total of 10 hub genes, including proteolipid Correspondence to: Professor Fubing Yang, Department of protein 1, myelin associated oligodendrocyte basic protein, Neurosurgery, The Affiliated Hospital of Southwest Medical contactin 2, myelin oligodendrocyte glycoprotein, myelin basic University, 25 Taiping Street, Jiangyang, Luzhou, Sichuan 646000, protein, myelin associated glycoprotein, SRY-box transcription P. R. Ch i na factor 10, C-X-C motif chemokine ligand 8 (CXCL8), vascular E-mail: [email protected] endothelial growth factor A (VEGFA) and plasmolipin, were identified. These hub genes were further subjected to GO term Abbreviations: GBM, glioblastoma; PBZ, peritumoral brain and KEGG pathway analysis, and were revealed to be enriched zone; TC, tumor core; rGBM, recurrent glioblastoma; GEO, Gene Expression Omnibus; DEGs, differentially expressed genes; in ‘central nervous system development’, ‘bladder cancer’ and GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and ‘rheumatoid arthritis’. These hub genes were used to perform Genomes; PPI, protein‑protein interaction; UP, upregulated; survival analysis using the GEPIA database, and it was deter- DOWN, downregulated; GEPIA, Gene Expression Profiling mined that VEGFA and CXCL8 were significantly associated Interactive Analysis; TCGA, The Cancer Genome Atlas; GTEx, with a reduction in the overall survival of patients with GBM. Genotype‑Tissue Expression; HR, hazard ratio; PLP1, proteolipid In conclusion, the results suggest that the recurrence of GBM protein 1; MOBP, myelin‑associated oligodendrocyte basic protein; is associated with high gene expression levels VEGFA and CNTN2, contactin 2; CXCL8, C‑X‑C motif chemokine ligand 8; CXCL8, and the development of the central nervous system. MOG, myelin oligodendrocyte glycoprotein; VEGFA, vascular endothelial growth factor A; MBP, myelin basic protein; MAG, Introduction myelin associated glycoprotein; SOX10, SRY‑box 10; PLLP, plasmolipin; IL‑8, interleukin 8; MMP2, matrix metalloproteinase 2; CXCR, C‑X‑C chemokine receptor; B1R, B1 bradykinin receptor; Originating from adult brain tissue, glioblastoma (GBM) is TMZ, temozolomide a highly malignant primary tumor with numerous charac- teristics, including complicated pathological diagnosis, poor Key words: peritumoral brain zone, tumor core, bioinformatics prognosis and easy relapse (1). Tumor cells have a strong analysis, recurrent glioblastoma, vascular endothelial growth ability for proliferation and invasion, and can invade the factor A, C-X-C motif chemokine ligand 8 central nervous system (2). In 2018, patients with GBM had a poor prognosis, and the median survival time of patients was ~17 months (3). In 2019, following standard treatment, the 6172 LUO et al: VEGFA AND CXCL8 GENES ARE ASSOCIATED WITH THE RECURRENCE OF GLIOBLASTOMA 6-month progression-free survival rate was 25.2% in patients Screening of DEGs. DEGs were screened using GEO2R with recurrent glioblastoma (rGBM) (4). Traditional treatment (https://www.ncbi.nlm.nih.gov/geo/geo2r/), which allowed a for GBM includes surgical resection, radiation and chemo- comparison of the differences between two different sets of therapy with temozolomide (5). Following surgical resection samples in a series. In the GSE13276 dataset, |log fold change of GBM, substantial invading tumor cells are located in the (FC)| ≥2 and P<0.05 were defined as statistically significant near resection edge of the tumor or within 2-3 cm from the for the DEGs. Similarly, in the GSE116520 dataset, |log FC| resection cavity, and these are the most common recurrence ≥1 (and P<0.05 were defined as statistically significant for the sites (6). DEGs). If the same criteria in the two datasets were selected, the In previous years, with the development of medicine and resulting genes would be limited, therefore in order to obtain a bioinformatics, gene expression information has been generated larger number of target genes different criteria were selected. and stored in the Gene Expression Omnibus (GEO) database. Excel software (Office 2016; Microsoft Corporation) was used Bioinformatics analysis allows an improved understanding to delete all genes without gene symbols and duplicate genes of the alterations in essential genes in the process of tumor corresponding to multiple probe IDs in the GSE13276 and development. Furthermore, it can provide a basis for target GSE116520 datasets. A Venn diagram of the DEGs obtained treatment and tumor diagnosis (7). A previous study identified from the bioinformatics and evolutionary genomics online tool that both the peritumoral brain zone (PBZ) and tumor core ‘Calculate and draw custom Venn diagrams’ (http://bioinfor- (TC) are heterogeneous in the same patients, and tumor cells matics.psb.ugent.be/webtools/Venn/) was constructed, and the in the PBZ exhibit increased invasiveness compared with cells common DEGs were identified. in the TC (8). Van Meter et al (9) demonstrated that there were a number of different gene expression products between the GO and KEGG enrichment analysis. GO (http://www. PBZ and TC. Even in the absence of tumor cells in the PBZ, geneontology.org) is a database used to describe the charac- it is possible to detect the expression of genes associated with teristics of genes and gene products. KEGG (https://www. invasion and neo-angiogenesis (10). Therefore, identifying kegg.jp/) is a database containing information on genome, differentially expressed genes (DEGs) between the PBZ chemistry and system functions (12). DAVID (version 6.8; and TC may reveal the causes of GBM recurrence, and may http://david.ncifcrf.gov/) is an online database, and was used provide a target for tumor treatment. to perform GO term and KEGG pathway enrichment anal- In the present study, the gene expression profiles of the yses (13,14). P<0.05 was considered to indicate a statistically PBZ were compared with the gene expression profiles of significant difference. the TC to identify DEGs. The DEGs of the PBZ and TC were screened by GEO2R online analysis, and the Database Interaction network analysis and hub gene identification. for Annotation, Visualization, and Integrated Discovery The STRING (https://string-db.org/) database is a tool for (DAVID) was used for Gene Ontology (GO) and Kyoto analyzing the interrelationships between genes, including direct Encyclopedia of Genes and Genomes (KEGG) enrichment (physical) and indirect (functional) links, and constructing PPI analyses. A protein-protein interaction (PPI) network was networks. STRING version 11.0 contains 24,584,628 proteins constructed using Search Tool for the Retrieval of Interacting from 5,090 organisms (15). The PPI network association Genes/Proteins (STRING) and Cytoscape software tools, among DEGs was analyzed using the STRING database and and the hub genes were obtained using the Cytoscape plug-in the default minimum required interaction score was set as Cytohubba. Furthermore, the Gene Expression Profiling >0.4. Subsequently, the Cytoscape (version 3.7.1; http://www. Interactive Analysis (GEPIA) database was used to analyze cytoscape.org/) plug‑in Cytohubba (version was 0.1; http://apps. the survival rate of patients with aberrant expression levels cytoscape.org/apps/cytohubba) was used to screen the PPI of the hub genes. network, and the top10 genes, which were the hub genes in the PBZ, were obtained using the Degree algorithm. Materials and methods Survival analysis.
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