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

Abstract

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.

• Authors: Markus Priller, Julia Pöschl, Leticia Abrão, André O von Bueren, Yoon-Jae Cho, Stefan Rutkowski, Hans A Kretzschmar, Ulrich Schüller
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 21 Pg. 6791-801 (Nov 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21918172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Biomarkers, Tumor
• FOXM1 protein, human
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• Peptides
• siomycin A

Topics

• Adolescent
• Adult
• Biomarkers, Tumor (biosynthesis, genetics)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Cerebellar Neoplasms (genetics, metabolism, pathology)
• Child
• Child, Preschool
• Forkhead Box Protein M1
• Forkhead Transcription Factors (antagonists & inhibitors, biosynthesis, genetics)
• Gene Expression Profiling
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Immunohistochemistry
• Infant
• Medulloblastoma (genetics, metabolism, pathology)
• Middle Aged
• Neoplasm Staging
• Peptides (pharmacology)
• Prognosis
• Young Adult