title: Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells.
abstract: BACKGROUND
  Glioblastoma (GBM) is the most lethal and common type of primary brain tumor. Recent evidence suggests that a subpopulation of GBM cells (glioblastoma stem cells [GSCs]) is critical for tumor progression, invasion, and therapeutic resistance. We and others have demonstrated that MET, a receptor tyrosine kinase, positively regulates the stemness phenotype and radioresistance of GSCs. Here, we interrogated the downstream effector pathways of MET signaling in GSCs.
  
  
  METHODS
  We have established a series of GSCs and xenograft tumors derived from freshly dissociated specimens from patients with GBM and characterized a subpopulation enriched with MET activation (MET(high/+)). Through global expression profiling and subsequent pathways analysis, we identified signaling pathways that are enriched in MET(high/+) populations, one of which is Wnt/β-catenin signaling pathway. To determine molecular interaction and the biological consequences of MET and Wnt/β-catenin signaling, we used pharmacological and shRNA-mediated genetic inhibition and performed various molecular and cellular analyses, including flow cytometry, immunohistochemistry, and clonogenicity assays.
  
  
  RESULTS
  We found that Wnt/β-catenin signaling is highly active in MET(high/+) cells, compared with bulk tumor cells. We also showed that Wnt/β-catenin signaling activities in GBM are directly modulated by the addition of ligand-mediated MET activation or MET inhibition. Furthermore, the ectopic expression of active-β-catenin (S37A and S45Y) rescued the phenotypic effects caused by MET inhibition.
  
  
  CONCLUSIONS
  These data suggest that Wnt/β-catenin signaling is a key downstream effector of MET signaling and contributes to the maintenance of GSC and GBM malignancy.
authors.affiliation: Department of Neurosurgery, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, South Korea.
authors.forename: Kang Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Jinguen
authors.initials: J
authors.lastname: Rheey
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Jin
authors.forename: Yeri
authors.initials: Y
authors.lastname: Lee
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D008156:Luciferases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met