Identification of CXCL8 as an Immune Microenvironment Regulator of Colorectal Cancer: A Bioinformatics Study Based on Cancer Genome Atlas and Gene Expression Omnibus Datasets

Abstract

BackgroundAt present, a lack of knowledge of the molecular mechanisms underlying the genesis and progression of colorectal cancer (CRC) exists. This is one of the reasons for poor prognosis of this increasingly occurring disease. The purpose of our research is to identify molecular candidates for therapeutic intervention that would help stop the malignant progression of CRC.MethodsIn this study, we performed bioinformatic analysis of the combined microarray data GSE40967 and GSE8671 in Gene Expression Omnibus (GEO) and the CRC RNA-seq dataset in The Cancer Genome Atlas (TCGA). This analysis consisted of 1067 CRC samples and 92 normal mucosae in total. We identified the common differentially expressed genes (DEGs) using R and Venn software. Protein–protein interaction (PPI) network information was obtained using the Search Tool for the Retrieval of Interacting Genes (STRING) Database. The Cytoscape plug-ins MCODE and cytoHubba were used to screen hub modules. CXCL8, which was the selected hub gene, was subjected to functional analysis and Gene Set Enrichment Analysis (GSEA). The algorithm “Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)” was employed to estimate the relative abundance of tumor infiltrating lymphocyte cells (TILs) with CXCL8 expression. Finally, correlation analysis was carried out to explore the underlying mechanisms.ResultsWe identified 135 common DEGs, which consisted of 38 upregulated genes and 97 downregulated genes. The upregulated DEGs were strikingly enriched in regulation of neutrophil chemotaxis and cytokine-cytokine receptor interaction. The downregulated DEGs were enriched in bicarbonate transport. We identified the candidate molecule CXCL8 as a product of the hub gene. Functional enrichment analysis and GSEA indicated that CXCL8 may be closely related to a regulator of the CRC immune microenvironment. Finally, TILs analysis and correlation analysis showed that CXCL8 may inhibit CD8+ T cell immune infiltration through the HIF-1α/PD-Ls axis. In addition, CXCL8 could induce the polarization of M2 macrophages through the PI3K/AKT3 pathway.ConclusionsWe determined that hub gene CXCL8 may promote immune escape of CRC by inhibiting CD8+ T cell immune infiltration or promoting polarization of M2 macrophages. CXCL8 is a potential therapeutic target for the treatment of CRC patients.