TNFSF15 suppresses VEGF production in endothelial cells by stimulating miR-29b expressionviaactivation of JNK-GATA3 signals

Abstract

Vascular endothelial cell growth factor (VEGF) plays a pivotal role in promoting neovascularization. VEGF gene expression in vascular endothelial cells in normal tissues is maintained at low levels but becomes highly up-regulated in a variety of disease settings including cancers. Tumor necrosis factor superfamily 15 (TNFSF15; VEGI; TL1A) is an anti-angiogenic cytokine prominently produced by endothelial cells in a normal vasculature. We report here that VEGF production in mouse endothelial cell line bEnd.3 can be inhibited by TNFSF15 via microRNA-29b (miR-29b) that targets the 3'-UTR of VEGF transcript. Blocking TNFSF15 activity by using either siRNA against the TNFSF15 receptor known as death domain-containing receptor-3 (DR3; TNFRSF25), or a neutralizing antibody 4-3H against TNFSF15, led to inhibition of miR-29b expression and reinvigoration of VEGF production. In addition, we found that TNFSF15 activated the JNK signaling pathway as well as the transcription factor GATA3, resulting in enhanced miR-29b production. Treatment of the cells either with SP600125, an inhibitor of JNK, or with JNK siRNA, led to eradication of TNFSF15-induced GATA3 expression. Moreover, GATA3 siRNA suppressed TNFSF15-induced miR-29b expression. These findings suggest that VEGF gene expression can be suppressed by TNFSF15-stimulated activation of the JNK-GATA3 signaling pathway which gives rise to up-regulation of miR-29b.

VEGI174 protein and its functional domain peptides exert antitumour effects on renal cell carcinoma

“…The VEGI174 protein and its domain peptides (V7 and V8) exhibited inhibitory effects on RCC proliferation, migration and invasion; however, the exact mechanism remains unclear. Zhang et al (38) reported that VEGF expression could be suppressed by VEGI-stimulated TNF superfamily member 15 activation of the Jun N-terminal kinase-GATA binding protein 3 signalling pathway. Qi et al (39) reported that VEGI inhibits vasculogenesis by regulating the relative levels of membrane-bound and soluble isoforms of VEGF receptor-1.…”

Protein of Vascular Endothelial Growth Inhibitor 174 Inhibits Epithelial–Mesenchymal Transition in Renal Cell Carcinoma In Vivo

“…The expression level of VEGF that was detected by IHC was significantly decreased in the VEGI174-treated group compared to the saline-treated group. Zhang et al reported that VEGF gene expression could be suppressed by TNFSF15 (VEGI)-stimulated activation of the Jun N-terminal kinase-GATA binding protein 3 (JNK-GATA3) signaling pathway (26). Qi et al found that VEGI inhibited vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1 (23).…”

Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15

“…We established an intracranial hemangioma model by injecting bEnd.3 cells into the right basal ganglia. The bEnd.3 cells, which exhibit low TNFSF15 and high VEGF expression levels (9,24), formed highly vascularized and extensively hemorrhagic vascular lesions in the 7 d following injection ( Fig. 2A).…”

“…TNFSF15 has been shown to be able to inhibit VEGF/VEGF receptor (VEGFR) 1-mediated, EPC-supported vasculogenesis (22) and to induce dephosphorylation of VEGFR2, thus blocking VEGF-induced, VEGFR2-mediated vascular hyperpermeability (23). Additionally, TNFSF15 suppresses VEGF production in endothelial cells by stimulating microRNA (miR)-29b expression (24,25), whereas VEGF suppresses TNFSF15 production in endothelial cells by stimulating miR-31 and miR-20a expression (24,25). Such a counterbalance of pro-and antiangiogenesis systems may be of significance in the maintenance of vascular homeostasis under physiologic conditions as well as the modulation of angiogenic microenvironment under pathologic conditions.…”