Expression of FoxM1 is required for the proliferation of medulloblastoma cells and indicates worse survival of patients

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, André O

AU - Cho, Yoon-Jae

AU - Rutkowski, Stefan

AU - Kretzschmar, Hans A

AU - Schüller, Ulrich

N1 - ©2011 AACR

PY - 2011/11/1

Y1 - 2011/11/1

N2 - PURPOSE: The transcription factor Forkhead box M1 (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: FoxM1 may be used as an additional prognostic marker and may represent a potential novel target to treat patients suffering from medulloblastoma.

AB - PURPOSE: The transcription factor Forkhead box M1 (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: FoxM1 may be used as an additional prognostic marker and may represent a potential novel target to treat patients suffering from medulloblastoma.

KW - Adolescent

KW - Adult

KW - Biomarkers, Tumor

KW - Cell Growth Processes

KW - Cell Line, Tumor

KW - Cerebellar Neoplasms

KW - Child

KW - Child, Preschool

KW - Forkhead Box Protein M1

KW - Forkhead Transcription Factors

KW - Gene Expression Profiling

KW - Gene Knockdown Techniques

KW - HEK293 Cells

KW - Humans

KW - Immunohistochemistry

KW - Infant

KW - Medulloblastoma

KW - Middle Aged

KW - Neoplasm Staging

KW - Peptides

KW - Prognosis

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/1078-0432.CCR-11-1214

DO - 10.1158/1078-0432.CCR-11-1214

M3 - SCORING: Journal article

C2 - 21918172

VL - 17

SP - 6791

EP - 6801

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 21

ER -