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. 2022 Oct 4:2022:5137301.
doi: 10.1155/2022/5137301. eCollection 2022.

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

Yongli Situ  1 , Xiaoyong Lu  1 , Yongshi Cui  1 , Qinying Xu  1 , Li Deng  1 , Hao Lin  2 , Zheng Shao  1 , Jv Chen  3
Affiliations

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

Yongli Situ et al. Biomed Res Int. .

Abstract

Background: Tumor angiogenesis plays a vital role in tumorigenesis, proliferation, and metastasis. Recently, vascular endothelial growth factor A (VEGFA) 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 CXCL1/2/3/5/6/8/11/16/17 and VEGFA were markedly overexpressed, while CXCL12/13/14 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: 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 considerably lower in patients with COAD, whereas methylation of CXCL5/6/12/14 and VEGFA was considerably higher. Furthermore, CXCL9/10/11 and VEGFA expression was notably 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 with dissimilar expression levels. CXC chemokines and VEGFA 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 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 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.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
The transcription of CXC chemokine-VEGFA network in COAD (UALCAN). (a1–m1) The transcription expression of CXCL1/2/3/5/6/8/11/12/13/14/16/17 and VEGFA in COAD based on sample types. (a2–m2) The transcription expression of CXCL1/2/3/5/6/8/11/12/13/14/16/17 and VEGFA in COAD based on the sex of the patient. (a3–m3) The transcription expression of CXCL1/2/3/5/6/8/11/12/13/14/16/17 and VEGFA in COAD based on individual cancer stages. Sample type denotes normal and patient groups. Gender denotes male and female. A Student's t-test was used for the comparative analysis, ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.
Figure 2
Figure 2
The protein expression of CXC chemokine-VEGFA network in COAD (Human Protein Atlas). (a1–h1) The protein expression of CXCL5/8/11/12/13/14/16 and VEGFA in normal colon tissue, respectively. (a2–h2) The protein expression of CXCL5/8/11/12/13/14/16 and VEGFA in COAD tissue, respectively. Note: the Human Protein Atlas database does not include immunohistochemical data for CXCL1/2/3/6/17 in COAD tissue.
Figure 3
Figure 3
Correlation between the pathological stage and different expressed CXC chemokine-VEGFA network of COAD patients (GEPIA): (a) CXCL9; (b) CXCL10; (c) CXCL11; (d) VEGFA. Notably, our results did not show statistically significant data. A Student's t-test was used for the comparative analysis.
Figure 4
Figure 4
The prognostic value of CXC chemokine-VEGFA network in COAD (GEPIA). The overall survival curve of (a) CXCL8 and (b) CXCL14. The disease-free survival of (c) CXCL11 and (d) VEGFA. Note: our results did not show statistically significant data.
Figure 5
Figure 5
Genetic alteration of CXC chemokine-VEGFA network in COAD (cBioPortal).
Figure 6
Figure 6
Promoter methylation of CXC chemokine-VEGFA network in COAD (UALCAN). (a) The promoter methylation level of CXCL1 in healthy individuals and COAD patients. (b) The promoter methylation level of CXCL2 in healthy individuals and COAD patients. (c) The promoter methylation level of CXCL3 in healthy individuals and COAD patients. (d) The promoter methylation level of CXCL5 in healthy individuals and COAD patients. (e) The promoter methylation level of CXCL6 in healthy individuals and COAD patients. (f) The promoter methylation level of CXCL11 in healthy individuals and COAD patients. (g) The promoter methylation level of CXCL12 in healthy individuals and COAD patients. (h) The promoter methylation level of CXCL13 in healthy individuals and COAD patients. (i) The promoter methylation level of CXCL14 in healthy individuals and COAD patients. (j) The promoter methylation level of CXCL17 in healthy individuals and COAD patients. (k) The promoter methylation level of VEGFA in healthy individuals and COAD patients. Note: our results did not show statistically significant data. A Student's t-test was used for the comparative analysis, ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001.
Figure 7
Figure 7
Interaction analyses of CXC chemokine-VEGFA network in COAD. (a) PPI network of CXC chemokine-VEGFA network in COAD (STRING). (b) Network and function analyses of CXC chemokine-VEGFA network in COAD (GeneMANIA).
Figure 8
Figure 8
GO function and KEGG pathway enrichment analyses of CXC chemokine-VEGFA network in COAD (Metascape). (a) Biological processes in COAD. (b) Molecular functions in COAD. (c) KEGG pathway analysis in COAD.
Figure 9
Figure 9
Genes differentially expressed in correlation with CXC chemokine-VEGFA network in COAD (LinkedOmics). (a1–m1) Pearson's correlation test was used to analyze correlations between CXCL1/2/3/5/6/8/11/12/13/14/16/17, VEGFA, and genes differentially expressed in COAD, respectively. (a2–m2, a3–m3) Heat maps showing genes positively and negatively correlated with CXCL1/2/3/5/6/8/11/12/13/14/16/17 and VEGFA in COAD, respectively (top 50 genes).
Figure 10
Figure 10
Gene expression correlation analysis of CXC chemokine-VEGFA network in COAD (LinkedOmics). The scatter plot shows Pearson's correlation of CXCL1 expression with expression of (a1) CXCL3, (a2) CXCL2, and (a3) ZC3H12A in COAD; Pearson's correlation of CXCL2 expression with expression of (b1) CXCL3, (a2) CXCL1, and (b2) ZC3H12A in COAD; Pearson's correlation of CXCL3 expression with expression of (a1) CXCL1, (b1) CXCL2, and (b3) ZC3H12A in COAD; Pearson's correlation of CXCL5 expression with expression of (c1) IL24, (c2) IL8, and (c3) MMP3 in COAD; Pearson's correlation of CXCL6 expression with expression of (d1) CXCL5, (d2) MMP3, and (d3) IL8 in COAD; Pearson's correlation of CXCL8 expression with expression of (e1) GPR109B, (e2) IL1B, and (e3) OSM in COAD; Pearson's correlation of CXCL11 expression with expression of (f1) CXCL10, (f2) UBD, and (f3) IDO1 in COAD; Pearson's correlation of CXCL12 expression with expression of (g1) NPR1, (g2) SLIT3, and (g3) SHE in COAD; Pearson's correlation of CXCL13 expression with expression of (h1) TIGIT, (h2) SH2D1A, and (h3) SIRPG in COAD; Pearson's correlation of CXCL14 expression with expression of (i1) D4S234E, (i2) TNFSF11, and (i3) COL9A1 in COAD; Pearson's correlation of CXCL16 expression with expression of (j1) ZMYND15, (j2) FLII, and (j3) NDEL1 in COAD; Pearson's correlation of CXCL17 expression with expression of (k1) FAM83A, (k2) GPR110, and (k3) SEMG1 in COAD; and Pearson's correlation of VEGFA expression with expression of (l1) GTPBP2, (l2) CCNL1, and (l3) CREBZF in COAD.
Figure 11
Figure 11
The correlation between CXC chemokine-VEGFA network and immune cell infiltration in COAD (TIMER): (a) CXCL1; (b) CXCL2; (c) CXCL3; (d) CXCL5; (e) CXCL6; (f) CXCL8; (g) CXCL11; (h) CXCL12; (i) CXCL13; (j) CXCL14; (k) CXCL16; (l) CXCL17; (m) VEGFA.
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