title: GLI2 is a potential therapeutic target in pediatric medulloblastoma.
abstract: To determine whether the zinc finger transcription factors GLI1 to GLI3 and suppressor of fused (SUFU) components of the Sonic hedgehog signaling pathway may be prognostic markers and potential therapeutic targets in pediatric medulloblastoma (MB), we investigated the relationship of the expression of these proteins to prognosis in the MB of 124 patients who had undergone surgery at the Hospital for Sick Children (Toronto, Ontario, Canada). The expressions of GLI1 (p = 0.011) and GLI2 (p = 0.003), but not of GLI3 (p = 0.774) or SUFU (p = 0.137), in the MB were associated with a worse overall survival by Kaplan-Meier analysis. Overall survival of patients positive for GLI1 and GLI2 was 6.01 ± 0.85 years and 5.27 ± 1.44 years, respectively, versus 10.11 ± 1.52 years and 10.18 ± 0.22 years for patients negative for GLI1 and GLI2, respectively. Knockdown of GLI2 in 3 MB cell lines resulted in decreased cell number and viability, as determined by the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay; knockdown of GLI1 had no effect. The decrease in cell number with GLI2 knockdown was caused by G0 cell cycle arrest; there was no induction of apoptosis. These results suggest that targeting the Sonic hedgehog pathway in positive patients may be a useful adjuvant therapeutic strategy for MB.
authors.affiliation: Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Canada.
authors.forename: Pawel
authors.initials: P
authors.lastname: Buczkowicz
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010372:Pediatrics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012189:Retrospective Studies; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: C400551:GLI1 protein, human; C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2