High ELK3 Expression is Associated with the VEGF-C/VEGFR-3 Axis and Gastric Tumorigenesis and Enhances Infiltration of M2 Macrophages

Abstract

Aim: To assess the expression and effect of ELK3 in gastric cancer, along with its associations with the VEGF-C/VEGFR-3 axis, IC₅₀ of the VEGFR-3 inhibitor axitinib and immune infiltration of M2-polarized macrophages in gastric cancer, and to analyze the possible epigenetic regulation mechanism. Materials & methods: Expression profiles and methylation data from 1645 samples were obtained and examined from multi-institutional public datasets. The associations were assessed by multiple analysis methods. Results: Elevated ELK3 is associated with the VEGF-C/VEGFR-3 axis and tumorigenesis, reduces the effect of axitinib in vitro, enhances immune infiltration of M2 macrophages and affects clinical outcomes. Hypomethylation contributes to the upregulation of ELK3 in gastric cancer. Conclusions:ELK3 is a potential therapeutic target which reduces the effect of axitinib and enhances infiltration of M2-polarized macrophages.

Keywords: :

• ELK3
• gastric cancer
• immune microenvironment
• poor prognosis
• VEGFR-3 inhibitor

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.futurescience.com/doi/suppl/10.4155/fmc-2019-0337

Acknowledgments

The results of this study are in whole or part based on data generated by multi public datasets including the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), the Human Protein Atlas (HPA), Kaplan–Meier plotter (KM plotter), the Gene Expression Profiling Interactive Analysis (GEPIA), Cancer Cell Line Encyclopedia (CCLE), Kyoto Encyclopedia of Genes and Genomes (KEGG), the Genomics of Drug Sensitivity in Cancer (GDSC) and the Gene Expression Omnibus dataset (GEO). Use of the databases in this study was performed in accordance with these dataset ethics and publication policy, as outlined in the TCGA (http://cancerge-nome.nih.gov/), GTEx (https://gtexportal.org/), HPA (http://www.proteinatlas.org/), KM plotter (http://www.kmplot.com), GEPIA (http://gepia.cancer-pku.cn/), CCLE (https://portals.broadinstitute.org/ccle), KEGG (https://www.kegg.jp/), GDSC (https://www.cancerrxgene.org/) and GEO (www.ncbi.nlm.nih.gov/geo/).

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.