title: TNFSF15 suppresses VEGF production in endothelial cells by stimulating miR-29b expression via activation 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.
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Kun
authors: K
authors: Zhang
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Hong-Xing
authors: HX
authors: Cai
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Shan
authors: S
authors: Gao
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Gui-Li
authors: GL
authors: Yang
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Hui-Ting
authors: HT
authors: Deng
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Guo-Ce
authors: GC
authors: Xu
authors: Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.|College of Life Sciences, Nankai University, Tianjin, China.
authors: Jihong
authors: J
authors: Han
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Qiang-Zhe
authors: QZ
authors: Zhang
authors: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.|Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China.
authors: Lu-Yuan
authors: LY
authors: Li
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000276:immunology / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D000873:Anthracenes; D057134:Antibodies, Neutralizing; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D042461:Vascular Endothelial Growth Factor A; C432165:pyrazolanthrone; D048055:Mitogen-Activated Protein Kinase 8
keywords: GATA3; angiogenesis; microRNA; tumor necrosis factor superfamily 15; vascular endothelial cell growth factor