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

Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide. Tumor necrosis factor α (TNF-α) 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 1α (HIF-1α) acts downstream of TNF-α in MCF-7 luminal breast cancer cells. However, whether vasodilator-stimulated phosphoprotein (VASP) is implicated in the direct regulation of HIF-1α in response to TNF-α 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-α. The results demonstrated that TNF-α decreased VASP expression by upregulating the expression of HIF-1α 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-1α lead to differential outcomes of overall survival in lung carcinoma. These results suggest that the HIF-1α/VASP signaling pathway serves an important function in the regulation of TNF-α-induced suppression of A549 cell proliferation and xenograft growth. This may improve our understanding of the antitumor effect of TNF-α.

Optimized 2-methoxyestradiol invasomes fortified with apamin: a promising approach for suppression of A549 lung cancer cells

“…TNF-α is a pleiotropic proinflammatory cytokine that regulates a variety of physiological and pathological signaling pathways including as inflammation, differentiation, proliferation, and apoptosis induction. TNF-α promotes cancer cell proliferation, migration, and adhesion in the tumor microenvironment, accelerating multistep cancer development (Liu et al., 2019 ).…”

Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

“…It was recently shown that under normoxic conditions stimulation of human intestinal epithelial Caco-2 cells with pro-inflammatory cytokines including TNF-α downregulated PHD1 mRNA levels which were correlated with decreased CCAAT-enhancer binding protein (C/EBPα) mRNA and protein expression, suggesting that the effect of TNF-α on the C/EBPα/PHD1 mechanism could lead to increased HIF-1α stabilization in the mucosal tissue of UC patients [ 12 ]. TNF-α treatment also significantly upregulates HIF-1α protein and mRNA levels in human squamous lung A549 and H226 cells, which inhibits A549 cell proliferation and adhesion as well as TNF-α-activated transcriptional activity of HIF-1α, resulting in suppression of vasodilator-stimulated phosphoprotein (VASP) and consequent inhibition of transplanted tumors growth in nude mice [ 64 ]. Taken together, TNF-α can be considered a modulator of the sensitivity of the HIF pathway to hypoxia in inflamed cells and its regulatory and constituent components, thus modulating protective HIF responses in different cell types and tissues.…”

Expression of Serum sLOX-1 in Patients with Non-Small-Cell Lung Cancer and Its Correlation with Lipid Metabolism

“…Zeya et al [ 11 ] found that LOX-1 interacts with its ligands to induce the expression of inflammatory cytokines such as IL-1 β and TNF- α . In addition, studies have found that IL-1 β promotes the invasion and metastasis of lung cancer A549 cell line, thereby promoting the progression and metastasis of cancer, and TNF- α could promote the metastasis of lung cancer by inducing EMT [ 28 , 29 ]. Studies have shown that LOX-1 participates in the cross presentation of antigens, exerts the targeted effect of immune activation and antigen transmission, inhibits the attack of the immune system, and promotes tumor progression [ 11 ].…”