TY - JOUR
T1 - Expression of FoxM1 is required for the proliferation of medulloblastoma cells and indicates worse survival of patients
AU - Priller, Markus
AU - Pöschl, Julia
AU - Abrão, Leticia
AU - Von Bueren, AndréO
AU - Cho, Yoon Jae
AU - Rutkowski, Stefan
AU - Kretzschmar, Hans A.
AU - Schüller, Ulrich
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Purpose: The transcription factor Forkhead boxM1(FoxM1) is a key regulator of cell-cycle progression. It is involved in the development of multiple organs, and we have previously reported on its important role for the mitotic entry of cerebellar granule neuron precursors. Constitutive expression of FoxM1 is required for the growth of multiple cancer types. This study aimed to determine its role in medulloblastoma, the most frequent malignant brain tumor in childhood that can derive from cerebellar granule neuron precursors. Experimental Design: We evaluated the expression of FoxM1 together with its prognostic value in two independent series of human medulloblastoma samples using immunohistochemistry (n = 43) and gene expression arrays (n = 193). The functional impact of FoxM1 expression was characterized by knockdown experiments in four human medulloblastoma cell lines, and the thiazole antibiotic siomycin A was tested to downregulate FoxM1 and inhibit tumor cell growth. Results: FoxM1 was highly expressed in all subtypes of medulloblastoma. Importantly, expression levels of FoxM1 significantly correlated with unfavorable clinical outcome in univariate analysis (P=0.0005), and FoxM1 was identified as an independent prognostic marker by multivariate analysis (P = 0.037). Knockdown of FoxM1 in medulloblastoma cell lines resulted in a significant decrease of cell viability which was caused by a failure in mitotic spindle formation and caspase-dependent mitotic catastrophe. Siomycin A significantly inhibited the expression of FoxM1 and the growth of medulloblastoma cells. Conclusions: FoxM1may be used as an additional prognosticmarker andmay represent a potential novel target to treat patients suffering from medulloblastoma.
AB - Purpose: The transcription factor Forkhead boxM1(FoxM1) is a key regulator of cell-cycle progression. It is involved in the development of multiple organs, and we have previously reported on its important role for the mitotic entry of cerebellar granule neuron precursors. Constitutive expression of FoxM1 is required for the growth of multiple cancer types. This study aimed to determine its role in medulloblastoma, the most frequent malignant brain tumor in childhood that can derive from cerebellar granule neuron precursors. Experimental Design: We evaluated the expression of FoxM1 together with its prognostic value in two independent series of human medulloblastoma samples using immunohistochemistry (n = 43) and gene expression arrays (n = 193). The functional impact of FoxM1 expression was characterized by knockdown experiments in four human medulloblastoma cell lines, and the thiazole antibiotic siomycin A was tested to downregulate FoxM1 and inhibit tumor cell growth. Results: FoxM1 was highly expressed in all subtypes of medulloblastoma. Importantly, expression levels of FoxM1 significantly correlated with unfavorable clinical outcome in univariate analysis (P=0.0005), and FoxM1 was identified as an independent prognostic marker by multivariate analysis (P = 0.037). Knockdown of FoxM1 in medulloblastoma cell lines resulted in a significant decrease of cell viability which was caused by a failure in mitotic spindle formation and caspase-dependent mitotic catastrophe. Siomycin A significantly inhibited the expression of FoxM1 and the growth of medulloblastoma cells. Conclusions: FoxM1may be used as an additional prognosticmarker andmay represent a potential novel target to treat patients suffering from medulloblastoma.
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U2 - 10.1158/1078-0432.CCR-11-1214
DO - 10.1158/1078-0432.CCR-11-1214
M3 - Article
C2 - 21918172
AN - SCOPUS:80455162327
SN - 1078-0432
VL - 17
SP - 6791
EP - 6801
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -