Systematic analysis of CXC chemokine–vascular endothelial growth factor A network in colonic adenocarcinoma from the perspective of angiogenesis

Abstract

Background Tumor angiogenesis plays a vital role in tumorigenesis, proliferation, and metastasis. Recently, it has been gradually recognized that VEGFA and CXC chemokines are important players in angiogenesis. It is interesting to explore the expression level, gene regulatory network, prognostic value, and target prediction of CXC chemokine-VEGFA network in colon adenocarcinoma (COAD) from the perspective of tumor angiogenesis. Methods In this study, we analyzed gene expression and regulation, prognostic value, target prediction, and immune infiltrates related to CXC chemokine-VEGFA network in patients with COAD using multiple databases (cBioPortal, UALCAN, Human Protein Atlas, GeneMANIA, GEPIA, TIMER, TRRUST, LinkedOmics, and Metascape). Results Our results showed that CXCL1/2/3/5/6/8/11/16/17 and VEGFA were significantly overexpressed, while CXCL12/13/14 was underexpressed in patients with COAD. Moreover, genetic alterations in the CXC chemokine-VEGFA network found at varying rates in patients with COAD were as follows: CXCL1/2/17 (2.1%), CXCL3/16 (2.6%), CXCL5/14 (2.4%), CXCL6 (3%), CXCL8 (0.8%), CXCL11/13 (1.9%), CXCL12 (0.6%), and VEGFA (1.3%). Promoter methylation of CXCL1/2/3/11/13/17 was significantly lower in patients with COAD, while methylation of CXCL5/6/12/14 and VEGFA was significantly higher. Furthermore, CXCL9/10/11 and VEGFA expression was significantly correlated with the pathological stages of COAD. In addition, patients with COAD with high CXCL8/11/14 or low VEGFA expression levels survived longer than patients without these characteristics. CXC chemokines and VEGFA form a complex regulatory network through co-expression, co-localization, and genetic interactions. Moreover, many transcription factor targets of the CXC chemokine-VEGFA network in patients with COAD were found: RELA, NFKB1, ZFP36, XBP1, HDAC2, SP1, ATF4, EP300, BRCA1, ESR1, HIF1A, EGR1, STAT3, and JUN. We further identified the top three miRNAs involved in regulating each CXC chemokine within the network: miR-518C, miR-369-3P, and miR-448 regulated CXCL1; miR-518C, miR-218, and miR-493 regulated CXCL2; miR-448, miR-369-3P, and miR-221 regulated CXCL3; miR-423 regulated CXCL13; miR-378, miR-381, and miR-210 regulated CXCL14; miR-369-3P, miR-382, and miR-208 regulated CXCL17; miR-486 and miR-199A regulated VEGFA. Furthermore, the CXC chemokine-VEGFA network in patients with COAD was significantly associated with immune infiltration. Conclusions This study revealed that the CXC chemokine-VEGFA network is a prognostic biomarker for patients with COAD. Moreover, our study provides new therapeutic targets for COAD which will act as a reference for further research in the future.

Systematic Analysis of CXC Chemokine–Vascular Endothelial Growth Factor A Network in Colonic Adenocarcinoma from the Perspective of Angiogenesis

“…The "Expression Analysis" module from the UALCAN database was utilized to examine TCGA gene expression data, and the following screening criteria were applied: (1) gene: CXC chemokines and VEGFA, (2) dataset: COAD, and (3) threshold setting conditions: P value cutoff = 0.05. A Student's t-test was used for the comparative analysis [14][15][16]. Data were obtained on February 14, 2022.…”

“…The expression of CXC chemokines and VEGFA, as well as the pathological stage of COAD, was analyzed using a Student's t-test. The prognosis of patients with COAD was analyzed using the Kaplan-Meier curve [14][15][16]. Data were obtained on February 15, 2022.…”

“…A z-score threshold of ±2.0 was used to calculate mRNA expression z-scores for all samples (log RNA Seq V2 RSEM). CXC chemokines and VEGFA were the chosen genes [14][15][16]. Data were obtained on February 15, 2022.…”

“…GeneMANIA (http://www .genemania.org) is a free online database that creates PPI networks and analyzes gene function [21]. The interaction networks were built using this database to explore the roles of CXC chemokines and VEGFA [14][15][16]. Data were obtained on February 16, 2022.…”

“…Metascape (https://metascape.org) is a free online gene function analysis tool that assists users in using current common bioinformatics analysis approaches to batch gene and protein analysis to predict function [22]. We conducted Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the CXC chemokine-VEGFA network in COAD using Metascape [14][15][16]. Data were obtained on February 17, 2022.…”