title: Aberrant activation of Hedgehog/Gli1 pathway on angiogenesis in gliomas.
abstract: BACKGROUND
  Hedgehog/Gli1 (HH/Gli1) pathway plays an important role in the patterning and development of the central nervous system during embryogenesis. Recent data have shown its potential involvement in a subset of human gliomas and inhibition of the pathway resulted in tumor suppression in both in vitro and in vivo studies. The underlying mechanisms of tumor suppression, however, remain to be fully elucidated.
  
  
  METHODS
  Gli1 expression was investigated in 60 surgically resected glioma tissues (World Health Organization (WHO) III-IV).
  
  
  RESULTS
  Gli1 was expressed in 43 gliomas with high Gli1 expression in nine cases, moderate expression in 21 cases, and low expression in 13 cases. Additionally, microvessel counts were higher in Gli1 positive gliomas than those in Gli1 negative gliomas. Gli1 expression in gliomas was positively correlated with microvessel density (MVD). To explore the molecular mechanisms of the phenotypic changes, we performed quantitative real-time polymerase chain reaction (PCR) and Western blot analysis to monitor the changes of a series of genes, which play critical roles in the regulation of glioma angiogenesis. In conclusion, HH/Gli1 pathway inhibition resulted in down-regulation of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) expressions, whereas this pathway activation led to up-regulation of VEGF, MMP2, and MMP9 expressions. These molecular changes of the HH/Gli1 pathway inhibited by indirect drug approach were consistent with Gli1 RNA-interference (RNAi) in glioma cell lines.
  
  
  CONCLUSIONS
  Our findings demonstrated that the aberrantly active HH/Gli1 pathway contributed to angiogenesis in part through induction of VEGF, MMP2, and MMP9.
authors.affiliation: Department of Neurosurgery, Tongji University School of Medicine, Shanghai, China.
authors.forename: Daming
authors.initials: D
authors.lastname: Cui
authors.forename: Xianzhen
authors.initials: X
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Yin
authors.forename: Wenhua
authors.initials: W
authors.lastname: Wang
authors.forename: Meiqing
authors.initials: M
authors.lastname: Lou
authors.forename: Shixin
authors.initials: S
authors.lastname: Gu
mesh_terms: D001932:Brain Neoplasms / Q000150:complications*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000150:complications*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology*; D000072079:Patched Receptors; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D004791:Enzyme Inhibitors; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C000541:cyclopamine