Abstract
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. 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. 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. FoxM1 may be used as an additional prognostic marker and may represent a potential novel target to treat patients suffering from medulloblastoma.
Highlights
Medulloblastoma is the most common malignant brain tumor in childhood with a 5-year overall survival rate of 66% [1]
Forkhead box M1 (FoxM1) was highly expressed in all subtypes of medulloblastoma
Expression levels of FoxM1 significantly correlated with unfavorable clinical outcome in univariate analysis (P 1⁄4 0.0005), and FoxM1 was identified as an independent prognostic marker by multivariate analysis (P 1⁄4 0.037)
Summary
Medulloblastoma is the most common malignant brain tumor in childhood with a 5-year overall survival rate of 66% [1]. While the cellular origin of medulloblastoma is uncertain for most of the 6 subgroups, tumors associated with pathologic Hedgehog signaling have recently been shown to arise from cerebellar granule neuron precursors [8]. During normal development, these precursors extensively proliferate due to a physiologic stimulation by Sonic hedgehog [9] until they migrate away from their mitotic niche in the external granule cell layer and differentiate at postnatal stages [10]. While the mechanisms of differentiation in cerebellar granule neurons are not yet clearly understood, it is evident that their cell-cycle progression is dependent on FoxM1 [11], which is a target gene of Hedgehog signaling [12, 13]
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