title: Myc-associated zinc finger protein (MAZ) is regulated by miR-125b and mediates VEGF-induced angiogenesis in glioblastoma.
abstract: In patients with glioblastomas, vascular endothelial growth factor (VEGF) is a key mediator of tumor-associated angiogenesis. Glioblastomas are notorious for their capacity to induce neovascularization, driving continued tumor growth. Here we report that miR-125b is down-regulated in glioblastoma-associated endothelial cells, resulting in increased expression of its target, myc-associated zinc finger protein (MAZ), a transcription factor that regulates VEGF. The down-regulation of miR-125b was also observed on exposure of endothelial cells to glioblastoma-conditioned medium or VEGF, resulting in increased MAZ expression. Further analysis revealed that inhibition of MAZ accumulation by miR-125b, or by MAZ-specific shRNAs, attenuated primary human brain endothelial cell migration and tubule formation in vitro, phenomena considered to mimick angiogenic processes in vitro. Moreover, MAZ expression was elevated in brain blood vessels of glioblastoma patients. Altogether these results demonstrate a functional feed-forward loop in glioblastoma-related angiogenesis, in which VEGF inhibits the expression of miR-125b, resulting in increased expression of MAZ, which in its turn causes transcriptional activation of VEGF. This loop is functionally impeded by the VEGF receptor inhibitor vandetanib, and our results may contribute to the further development of inhibitors of tumor-angiogenesis.
authors.affiliation: Neuro-oncology Research Group, Department of Neurosurgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Smits
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
authors.forename: Bert
authors.initials: B
authors.lastname: van het Hof
authors.forename: Joost A R
authors.initials: JA
authors.lastname: Drexhage
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
mesh_terms: D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D005909:Glioblastoma / Q000098:blood supply* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C076035:c-MYC-associated zinc finger protein