title: Hedgehog signaling in glioblastoma multiforme.
abstract: Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults with a median survival of 14.6 mo under the best available treatment. New treatment strategies are therefore urgently required, for which a profound understanding of tumor biology is necessary. Much effort has been devoted to tumor-specific aberrant signaling processes. Recently it was discovered that the transcription factor Gli1, which is activated by hedgehog signaling, is a highly predictive marker in GBM, as determined by immunohistochemistry. To determine whether GBM cells have transcriptionally active Gli1, we performed experiments with reporter genes with cells isolated from surgically removed human tumors and cell lines. We also determined whether the hedgehog signaling inhibitor cyclopamine influences reporter gene expression and cell viability, and we determined the expression of Gli1, SHH and Patched1 by quantitative real-time RT-PCR. Reporter gene analysis of nine cultures and four cell lines demonstrated a significantly enhanced transcriptional activity in six tumor cell cultures and all cell lines. Analysis of cell viability in the presence of cyclopamine revealed a response of all cell cultures with the exception of one primary culture and one cell line, but only one cell line responded to cyclopamine with reduced hedgehog signaling activity. This indicates that the toxicity of cyclopamine toward GBM cells is independent from hedgehog signaling. Since no correlation between hedgehog activity and SHH, Gli1 and Patched1 mRNA levels was observed we conclude that other mechanisms aside from transcriptional regulation of these factors are responsible for hedgehog activity in tumor cells derived from GBM.
authors.affiliation: Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Leipzig AöR, Leipzig, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Braun
authors.forename: Henry
authors.initials: H
authors.lastname: Oppermann
authors.forename: Antje
authors.initials: A
authors.lastname: Mueller
authors.forename: Christof
authors.initials: C
authors.lastname: Renner
authors.forename: Amalya
authors.initials: A
authors.lastname: Hovhannisyan
authors.forename: Rainer
authors.initials: R
authors.lastname: Baran-Schmidt
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.forename: Alan
authors.initials: A
authors.lastname: Hipkiss
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.forename: Jürgen
authors.initials: J
authors.lastname: Meixensberger
authors.forename: Frank
authors.initials: F
authors.lastname: Gaunitz
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005909:Glioblastoma / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine