JNK/AP-1 pathway is involved in tumor necrosis factor-α induced expression of vascular endothelial growth factor in MCF7 cells

Abstract

Vascular endothelial growth factor (VEGF) has been implicated in breast tumor angiogenesis. And tumor necrosis factor-α (TNF-α) is a positive regulator of VEGF. This study was aimed to identify the signalling pathway of TNF-α in VEGF expression regulation in breast cancer cell line MCF7. Using luciferase reporter assays, we demonstrated that TNF-α significantly increased activator protein-1 (AP-1) transcriptional activity in the MCF7 cells. The expression of the AP-1 family members c-Jun, c-Fos and JunB and phosphorylation levels of c-Jun were upregulated by TNF-α, whereas other AP-1 family members Fra-1, Fra-2, and JunD were unaffected. The activation of AP-1 was associated with the formation of p-c-Jun-c-Jun and p-c-Jun-JunB homodimers. Furthermore, the phosphorylation levels of c-Jun N-terminal kinase (JNK) but not P38 and ERK were elevated by TNF-α in MCF7 cells. TNF-α potently upregulated the mRNA and protein levels of VEGF, which were significantly reversed by JNK inhibitor SP600125. Finally using chromatin immunoprecipitation (CHIP) assays, we found that p-c-Jun bound to the VEGF promoter and regulated VEGF transcription directly. These data suggest that the pro-inflammatory cytokine TNF-α is a critical regulator of VEGF expression in breast cancer cells, at least partially via a JNK and AP-1 dependent pathway.

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

“…[35][36][37] Furthermore, VEGF expression was found to be markedly increased and correlated with microvessel density in nasopharyngeal carcinoma patients. 30 Similarly, we herein found that TNFAIP2 is a downstream target of TNFa that acts as a potential angiogenic factor, as shown by the association of its expression with microvessel density in vivo.…”

Heme Oxygenase-1/Carbon Monoxide Induces Vascular Endothelial Growth Factor Expression via p38 Kinase-dependent Activation of Sp1

“…Erk activation mediates VEGF gene transcription following Ras induction or growth factor stimulation (20,21). Moreover, activation of JNK and p38 following cytokine or growth factor stimulation leads to increased VEGF expression by increasing the stability of its mRNA or gene transcription (22)(23)(24)(25)(26)(27). The VEGF promoter contains several potential binding sites for transcriptional factors, including hypoxia-inducible factor-1, Sp1, AP1, and AP2 (1).…”

Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group Study

“…Thalidomide inhibits expression of the pro-angiogenic factors VEGF and basic fibroblast growth factor (bFGF) via mechanisms involving tumor necrosis factor-alpha (TNFalpha) [12,[30][31][32] and transcriptional activation of the VEGF promoter [33]. Tamoxifen inhibits angiogenesis and VEGF by ER-dependent [6,11] and -independent mechanisms [32].…”