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. 2025 Sep-Oct;22(5):791-808.
doi: 10.21873/cgp.20537.

Identification of CXCL8, IL1A, and IL1B as Hub Genes of Therapeutic Resistance in Glioblastoma Multiforme via Bioinformatics Analysis

Sujin Lee  1 , Jungwook Roh  2 , Goeun Yoon  1 , Jihoon Kang  3 , Buhyun Youn  4 , Wanyeon Kim  5   6
Affiliations

Identification of CXCL8, IL1A, and IL1B as Hub Genes of Therapeutic Resistance in Glioblastoma Multiforme via Bioinformatics Analysis

Sujin Lee et al. Cancer Genomics Proteomics. 2025 Sep-Oct.

Abstract

Background/aim: Glioblastoma multiforme (GBM) is a highly aggressive, treatment-resistant brain tumor with a dismal prognosis, and identifying key molecules involved in its therapeutic resistance is essential to improve patient outcomes. This study was undertaken to identify hub genes associated with the radioresistance and temozolomide (TMZ) resistance of GBM using bioinformatics analysis.

Materials and methods: RNA-seq and microarray datasets from the GEO database were analyzed to identify differentially expressed genes (DEGs). GO and KEGG pathway enrichment analyses were performed using Enrichr. A protein-protein interaction (PPI) network was constructed using STRING and visualized with Cytoscape, and hub genes were identified by MCODE analysis. Expression and survival analyses were conducted on TCGA and GTEx datasets using GEPIA2.

Results: Twenty-four DEGs were considered linked to radioresistance and 122 to TMZ resistance. Functional enrichment and PPI network analyses highlighted key therapeutic resistance pathways, including cytokine-mediated signaling and inflammatory response pathways. Notably, CXCL8, IL1A, and IL1B were identified as key hub genes significantly enriched in these pathways. Expression analysis confirmed their up-regulation in GBM, and survival analysis indicated their association with prognosis.

Conclusion: This study identifies CXCL8, IL1A, and IL1B as potential therapeutic targets for overcoming the resistance of GBM to radiotherapy and chemotherapy. In addition, these genes might serve as prognostic biomarkers and key regulators of GBM malignancy. Future studies are warranted to explore their functional roles in vivo and assess their potential use as therapeutic intervention targets.

Keywords: CXCL8; IL1A; IL1B; glioblastoma; therapeutic resistance.

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Conflict of interest statement

The Authors declare that there are no conflicts of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Workflow for identifying genes significantly involved in the therapeutic resistance of glioblastoma multiforme (GBM) by bioinformatics analysis.
Figure 2
Figure 2
Identification of differentially expressed genes (DEGs) in glioblastoma multiforme (GBM). (A-E) Volcano plots of gene expression profile data of DEGs. GSE207002 (A), GSE56937 (B), and GSE240377 (C) were found to be associated with radioresistance, and GSE229600 (D) and GSE240377 (E) with temozolomide (TMZ) resistance. Blue and red dots represent down- and up-regulated genes, respectively. (F) Venn diagrams show 24 overlapping radioresistance-related DEGs. (G) Venn diagrams show a total of 122 overlapping TMZ resistance-related DEGs, including 117 up-regulated and 5 down-regulated DEGs. (H) Venn diagrams show 5 DEGs overlapping when comparing (F) and (G).
Figure 3
Figure 3
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapped differentially expressed genes (DEGs). Bar graphs show GO terms of (A) 24 radioresistance-related DEGs and (B) 122 TMZ resistance-related DEGs. KEGG pathways are presented as dot plots for (C) 24 radioresistance-related DEGs and (D) 122 TMZ resistance-related DEGs.
Figure 3
Figure 3
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapped differentially expressed genes (DEGs). Bar graphs show GO terms of (A) 24 radioresistance-related DEGs and (B) 122 TMZ resistance-related DEGs. KEGG pathways are presented as dot plots for (C) 24 radioresistance-related DEGs and (D) 122 TMZ resistance-related DEGs.
Figure 3
Figure 3
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapped differentially expressed genes (DEGs). Bar graphs show GO terms of (A) 24 radioresistance-related DEGs and (B) 122 TMZ resistance-related DEGs. KEGG pathways are presented as dot plots for (C) 24 radioresistance-related DEGs and (D) 122 TMZ resistance-related DEGs.
Figure 3
Figure 3
Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapped differentially expressed genes (DEGs). Bar graphs show GO terms of (A) 24 radioresistance-related DEGs and (B) 122 TMZ resistance-related DEGs. KEGG pathways are presented as dot plots for (C) 24 radioresistance-related DEGs and (D) 122 TMZ resistance-related DEGs.
Figure 4
Figure 4
Protein-protein interaction (PPI) network and Molecular Complex Detection (MCODE) analysis of differentially expressed genes (DEGs). (A) The PPI network was constructed with overlapped radioresistance-related DEGs from three Gene Expression Omnibus (GEO) datasets (GSE207002, GSE56937, and GSE240377). (B) The PPI network was constructed using overlapped TMZ resistance-related DEGs from two GEO datasets (GSE229600 and GSE240377). (C, D) The modules of (A) and (B), respectively, are shown using MCODE at a cutoff degree of 10.
Figure 5
Figure 5
The expression levels of hub genes in glioblastoma multiforme (GBM) tissues compared to normal tissues were analyzed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Relative expression level of (A) C-X-C motif chemokine ligand 8 (CXCL8), (B) interleukin-1 alpha (IL1A), and (C) interleukin-1 beta (IL1B) in GBM compared to normal tissue. (D) Relative co-expression of CXCL8, IL1A, and IL1B in GBM compared to normal tissue. The red box plot represents tumor tissues, and the black box plot represents normal tissues. *p<0.05.
Figure 6
Figure 6
Overall survival curves for hub genes in glioblastoma multiforme (GBM) and low-grade glioma (LGG) patients were analyzed using GEPIA2. A comparison of survival rates in the high and low (A) CXCL8, (B) IL1A, and (C) IL1B expression groups. (D) A comparison of survival rates in the high and low combined CXCL8, IL1A, and IL1B groups.
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References

    1. Gallego O. Nonsurgical treatment of recurrent glioblastoma. Curr Oncol. 2015;22(4):e273–e281. doi: 10.3747/co.22.2436. - DOI - PMC - PubMed
    1. Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neuro Oncol. 2022;24(Suppl 5):v1–v95. doi: 10.1093/neuonc/noac202. - DOI - PMC - PubMed
    1. Ali MY, Oliva CR, Noman ASM, Allen BG, Goswami PC, Zakharia Y, Monga V, Spitz DR, Buatti JM, Griguer CE. Radioresistance in glioblastoma and the development of radiosensitizers. Cancers (Basel) 2020;12(9):2511. doi: 10.3390/cancers12092511. - DOI - PMC - PubMed
    1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. doi: 10.1056/NEJMoa043330. - DOI - PubMed
    1. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol. 2002;20(5):1375–1382. doi: 10.1200/jco.2002.20.5.1375. - DOI - PubMed

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