TNF- a Secreted from Macrophages Increases the Expression of Prometastatic Integrin aV in Gastric Cancer

The tumor microenvironment comprising blood vessels, fibroblasts, immune cells, and the extracellular matrix surrounding cancer cells, has recently been targeted for research in cancer therapy. We aimed to investigate the effect of macrophages on the invasive ability of gastric cancer cells, and studied their potential mechanism. In transcriptome analysis, integrin alpha V was identified as a gene increased in AGS cells cocultured with RAW264.7 cells. AGS cells cocultured with RAW264.7 cells displayed increased adhesion to the extracellular matrix and greater invasiveness compared with AGS cells cultured alone. This increased invasion of AGS cells cocultured with RAW264.7 cells was inhibited by integrin alpha V knockdown. In addition, the increase in integrin alpha V expression induced by tumor necrosis factor-alpha (TNF-alpha) or by coculture with RAW264.7 cells was inhibited by TNF receptor 1 (TNFR1) knockdown. The increase in integrin alpha V expression induced by TNF-alpha was inhibited by both Mitogen-activated protein kinase (MEK) inhibitor and VGLL1 S84 peptide treatment. Finally, transcription of integrin alpha V was shown to be regulated through the binding of VGLL1 and TEAD4 to the promoter of integrin alpha V. In conclusion, our study demonstrated that TNFR1-ERK-VGLL1 signaling activated by TNF-alpha secreted from RAW264.7 cells increased integrin alpha V expression, thereby increasing the adhesion and invasive ability of gastric cancer cells.