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

BACKGROUND

Tumor angiogenesis plays a vital role in tumorigenesis, proliferation, and metastasis. Recently, vascular endothelial growth factor A () and CXC chemokines have been shown to play vital roles in angiogenesis. Exploring the expression level, gene regulatory network, prognostic value, and target prediction of the CXC chemokine-VEGFA network in colon adenocarcinoma (COAD) is crucial 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 the CXC chemokine-VEGFA network in patients with COAD using multiple databases (cBioPortal, UALCAN, Human Protein Atlas, GeneMANIA, GEPIA, TIMER (version 2.0), TRRUST (version 2), LinkedOmics, and Metascape).

RESULTS

Our results showed that and were markedly overexpressed, while were 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: (2.1%), (2.6%), (2.4%), (3%), (0.8%), (1.9%), (0.6%), and (1.3%). Promoter methylation of was considerably lower in patients with COAD, whereas methylation of and was considerably higher. Furthermore, and expression was notably correlated with the pathological stages of COAD. In addition, patients with COAD with high or low expression levels survived longer than patients with dissimilar expression levels. CXC chemokines and form a complex regulatory network through coexpression, colocalization, and genetic interactions. Moreover, many transcription factor targets of the CXC chemokine-VEGFA network in patients with COAD were identified: 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 ; miR-518C, miR-218, and miR-493 regulated ; miR-448, miR-369-3P, and miR-221 regulated ; miR-423 regulated ; miR-378, miR-381, and miR-210 regulated ; miR-369-3P, miR-382, and miR-208 regulated ; miR-486 and miR-199A regulated . Furthermore, the CXC chemokine-VEGFA network in patients with COAD was notably associated with immune infiltration.

CONCLUSIONS

This study revealed that the CXC chemokine-VEGFA network might act as a prognostic biomarker for patients with COAD. Moreover, our study provides new therapeutic targets for COAD, serving as a reference for further research in the future.