title: Vascular endothelial growth factor suppresses TNFSF15 production in endothelial cells by stimulating miR-31 and miR-20a expression via activation of Akt and Erk signals.
abstract: Tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) is a negative modulator of angiogenesis for blood vessel homeostasis and is produced by endothelial cells in a mature vasculature. It is known to be downregulated by vascular endothelial growth factor (VEGF), a major regulator of neovascularization but the mechanism of this interaction is unclear. Here we report that VEGF is able to stimulate the production of two microRNAs, miR-20a and miR-31, which directly target the 3'-UTR of TNFSF15. Additionally, we show that two VEGF-stimulated cell growth signals, Erk and Akt, are responsible for promoting the expression of miR-20a and miR-31. Treatment of human umbilical vein endothelial cells (HUVECs) with Akt inhibitor LY294002 results in diminished miR-20a and miR-31 production, while Erk inhibitor U0126 prevented VEGF-stimulated expression of miR-20a but not that of miR-31. Furthermore, inactivation of either Erk or Akt signals restores TNFSF15 gene expression. In an angiogenesis assay, elevated miR-20a or miR-31 levels in HUVECs leads to enhancement of capillary-like tubule formationin vitro, whereas lowered miR-20a and miR-31 levels results in an inhibition. These findings are consistent with the view that miR-20a and miR-31 mediate VEGF-induced downregulation of TNFSF15. Targeting these microRNA molecules may therefore provide an effective approach to inhibit angiogenesis.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Zhai
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Guo-Ce
authors.initials: GC
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Qiang-Zhe
authors.initials: QZ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research Nankai University China; Collaborative Innovation Center for Biotherapy Nankai University West China Hospital Sichuan University Chengdu China.
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
keywords: Akt; Erk; TNFSF15; VEGF; miRNA