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P aired box gene 8 ( PAX8 ) expression is associated with sonic hedgehog ( SHH )/wingless int ( WNT ) subtypes, desmoplastic histology and patient survival in human medulloblastomas
Author(s) -
Harter Patrick N.,
Baumgarten Peter,
Zinke Jenny,
Schilling Karl,
Baader Stefan,
Hartmetz AnnKathrin,
Schittenhelm Jens,
Beschorner Rudi,
Liebner Stefan,
Schulte Dorothea,
Plate KarlHeinz,
Gutwein Paul,
Korshunov Andrey,
Pfister Stefan M.,
Jones David T. W.,
Doberstein Kai,
Mittelbronn Michel
Publication year - 2015
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12186
Subject(s) - biology , sonic hedgehog , forebrain , microbiology and biotechnology , pathology , central nervous system , endocrinology , medicine , signal transduction
Aims The paired box gene 8 ( PAX 8) 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 ( MB s) ( n = 113) for PAX 8 expression by immunohistochemistry. Human MB cell lines were assessed for PAX 8 expression using polymerase chain reaction and immunoblotting and analysed for growth and migration following PAX 8 knock‐down by small interfering ribonucleic acid (si RNA ). Results PAX 8 protein expression was associated with germinal layers in human and murine forebrain and hindbrain development. PAX 8 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 PAX 8 expression with sonic hedgehog ( SHH ) and wingless int subtypes but not with group 3 and 4 MB s. Beyond that, we detected high PAX 8 levels in desmoplastic MB subtypes. Univariate analyses revealed high PAX 8 levels as a prognostic factor associated with a significantly better patient prognosis in human MB (overall survival: L og‐ R ank P = 0.0404, Wilcoxon P = 0.0280; progression‐free survival: L og‐ R ank P = 0.0225; W ilcoxon P = 0.0136). In vitro assays revealed increased proliferation and migration of MB cell lines after PAX 8 si RNA knock‐down. Conclusion In summary, high PAX 8 expression is linked to better prognosis in MB s potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio‐temporal expression pattern of PAX 8 during brain development might contribute to the understanding of distinct MB subtype histogenesis.