title: The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis.
abstract: We recently discovered that truncated glioma-associated oncogene homolog 1 (TGLI1) is highly expressed in glioblastoma (GBM) and linked to increased GBM vascularity. The mechanisms underlying TGLI1-mediated angiogenesis are unclear. In this study, we compared TGLI1- with GLI1-expressing GBM xenografts for the expression profile of 84 angiogenesis-associated genes. The results showed that expression of six genes were upregulated and five were down-regulated in TGLI1-carrying tumors compared to those with GLI1. Vascular endothelial growth factor-C (VEGF-C) and tumor endothelial marker 7 (TEM7) were selected for further investigations because of their significant correlations with high vascularity in 135 patient GBMs. TGLI1 bound to both VEGF-C and TEM7 gene promoters. Conditioned medium from TGLI1-expressing GBM cells strongly induced tubule formation of brain microvascular endothelial cells, and the induction was prevented by VEGF-C/TEM7 knockdown. Immunohistochemical analysis of 122 gliomas showed that TGLI1 expression was positively correlated with VEGF-C, TEM7 and microvessel density. Analysis of NCBI Gene Expression Omnibus datasets with 161 malignant gliomas showed an inverse relationship between tumoral VEGF-C, TEM7 or microvessel density and patient survival. Together, our findings support an important role that TGLI1 plays in GBM angiogenesis and identify VEGF-C and TEM7 as novel TGLI1 target genes of importance to GBM vascularity.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Carpenter
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Paw
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Sherona
authors.initials: S
authors.lastname: Sirkisoon
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Debinski
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.|Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Lo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis* / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D009363:Neoplasm Proteins; C510620:PLXDC1 protein, human; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D000071676:Zinc Finger Protein GLI1
keywords: GLI1; TGLI1; VEGF-C; angiogenesis; glioblastoma