TY  - JOUR
AU  - Harter, Patrick
AU  - Baumgarten, Peter
AU  - Zinke, Jenny
AU  - Schilling, Karl
AU  - Baader, Stefan
AU  - Hartmetz, Ann-Kathrin
AU  - Schittenhelm, Jens
AU  - Beschorner, Rudi
AU  - Liebner, Stefan
AU  - Schulte, Dorothea
AU  - Plate, Karl-Heinz
AU  - Gutwein, Paul
AU  - Korshunov, Andrey
AU  - Pfister, Stefan
AU  - Jones, David
AU  - Doberstein, Kai
AU  - Mittelbronn, Michel
TI  - Paired box gene 8 (PAX8) expression is associated with sonic hedgehog (SHH)/wingless int (WNT) subtypes, desmoplastic histology and patient survival in human medulloblastomas.
JO  - Neuropathology & applied neurobiology
VL  - 41
IS  - 2
SN  - 0305-1846
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DKFZ-2017-02698
SP  - 165 - 179
PY  - 2015
AB  - 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.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).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.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.
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - PAX8 Transcription Factor (NLM Chemicals)
KW  - PAX8 protein, human (NLM Chemicals)
KW  - Paired Box Transcription Factors (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - SHH protein, human (NLM Chemicals)
KW  - Wnt Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25287489
DO  - DOI:10.1111/nan.12186
UR  - https://inrepo02.dkfz.de/record/126670
ER  -