title: Paired box gene 8 (PAX8) expression is associated with sonic hedgehog (SHH)/wingless int (WNT) subtypes, desmoplastic histology and patient survival in human medulloblastomas.
abstract: OBJECTIVE
  The paired box gene 8 (PAX8) plays crucial roles in organ patterning and cellular differentiation during development and tumorigenesis. Although its function is partly understood in vertebrate development, there is poor data concerning human central nervous system (CNS) development and brain tumours.
  
  
  METHODS
  We investigated developing human (n = 19) and mouse (n = 3) brains as well as medulloblastomas (MBs) (n = 113) for PAX8 expression by immunohistochemistry. Human MB cell lines were assessed for PAX8 expression using polymerase chain reaction and immunoblotting and analysed for growth and migration following PAX8 knock-down by small interfering ribonucleic acid (siRNA).
  
  
  RESULTS
  PAX8 protein expression was associated with germinal layers in human and murine forebrain and hindbrain development. PAX8 expression significantly decreased over time in the external granule cell layer but increased in the internal granule cell layer. In MB subtypes, we observed an association of PAX8 expression with sonic hedgehog (SHH) and wingless int subtypes but not with group 3 and 4 MBs. Beyond that, we detected high PAX8 levels in desmoplastic MB subtypes. Univariate analyses revealed high PAX8 levels as a prognostic factor associated with a significantly better patient prognosis in human MB (overall survival: Log-Rank P = 0.0404, Wilcoxon P = 0.0280; progression-free survival: Log-Rank P = 0.0225; Wilcoxon P = 0.0136). In vitro assays revealed increased proliferation and migration of MB cell lines after PAX8 siRNA knock-down.
  
  
  CONCLUSIONS
  In summary, high PAX8 expression is linked to better prognosis in MBs potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio-temporal expression pattern of PAX8 during brain development might contribute to the understanding of distinct MB subtype histogenesis.
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.forename: Jenny
authors.initials: J
authors.lastname: Zinke
authors.forename: Karl
authors.initials: K
authors.lastname: Schilling
authors.forename: Stefan
authors.initials: S
authors.lastname: Baader
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Hartmetz
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.forename: Rudi
authors.initials: R
authors.lastname: Beschorner
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebner
authors.forename: Dorothea
authors.initials: D
authors.lastname: Schulte
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Plate
authors.forename: Paul
authors.initials: P
authors.lastname: Gutwein
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Kai
authors.initials: K
authors.lastname: Doberstein
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D000293:Adolescent; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis*; D011379:Prognosis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D034741:RNA, Small Interfering; C509239:SHH protein, human; D051153:Wnt Proteins
keywords: PAX8; SHH; WNT; cerebellar development; medulloblastoma