TNF-alpha inhibits xenograft tumor formation by A549 lung cancer cells in nude mice via the HIF-1 alpha/VASP signaling pathway

摘要

Lung cancer is the leading cause of cancer-associated mortality worldwide. Tumor necrosis factor alpha (TNF-alpha) is an important cytokine in the tumor microenvironment that serves a function in the balance of cell survival and cell death pathways. Our previous studies indicated that hypoxia-inducible factor 1 alpha (HIF-1 alpha) acts downstream of TNF-alpha in MCF-7 luminal breast cancer cells. However, whether vasodilator-stimulated phosphoprotein (VASP) is implicated in the direct regulation of HIF-1 alpha in response to TNF-alpha in lung cancer remains unknown. In vitro studies were performed using A549 and H226 lung carcinoma cells and in vivo studies of tumor xenograft models were performed to investigate the effects of TNF-alpha. The results demonstrated that TNF-alpha decreased VASP expression by upregulating the expression of HIF-1 alpha to inhibit A549 cell proliferation and adhesion. Inhibition of transplanted tumor growth was associated with downregulation of VASP expression in nude mice. Bioinformatics analysis indicated that expression levels of VASP or HIF-1 alpha lead to differential outcomes of overall survival in lung carcinoma. These results suggest that the HIF-1 alpha/VASP signaling pathway serves an important function in the regulation of TNF-alpha-induced suppression of A549 cell proliferation and xenograft growth. This may improve our understanding of the antitumor effect of TNF-alpha.