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 ¼ 43) and gene expression arrays (n ¼ 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 ¼ 0.0005), and FoxM1 was identified as an independent prognostic marker by multivariate analysis (P ¼ 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. Clin Cancer Res; 17(21); 6791-801. Ó2011 AACR.

Inhibition of FOXM1 by thiostrepton sensitizes medulloblastoma to the effects of chemotherapy

“…Similar results were obtained with RNAi-mediated inhibition of FOXM1 in Daoy cells. These results support the idea proposed by Priller et al (12) that FOXM1 inhibition results in failure of mitosis and leads to mitotic catastrophe in MB. Furthermore, our results demonstrated the efficient antitumor activity of thiostrepton in Daoy cells and suggest that the effects of thiostrepton may depend on the downregulation of FOXM1 target genes, which have been shown to be involved in the regulation of cell growth, apoptosis, cell cycle and progression (10).…”

“…Elevated expression of FOXM1 has been detected in a wide range of human tumors and has been implicated in cellular transformation, tumor initiation and progression (7). Accumulating evidence demonstrates that increased expression of FOXM1 is associated with poor prognosis in various types of cancers (8)(9)(10)(11), including MB (12). Furthermore, previous studies have shown that FOXM1 mediates resistance to a diverse spectrum of anticancer drugs in breast cancer (13)(14)(15).…”

Development of the cerebellum: simple steps to make a ‘little brain’

“…Although Wnt signalling also affects cerebellar proliferation, its effects are restricted to non-granule cells (Pei et al, 2012;Selvadurai and Mason, 2012) and accordingly the Wnt-dependent subgroup of tumours, along with some Shh subgroup tumours , appears to have a hindbrain origin (Gibson et al, 2010). Pathways that might supress transit amplification, such as BMP signalling (SMAD) (Aref et al, 2013), or promote differentiation (Barhl1) are thus associated with improved patient prognosis (Poschl et al, 2011), in contrast to those associated with regulating granule cell precursor identity (Atoh1) (Schuller et al, 2008;Yang et al, 2008) or proliferation (Foxm1) (Schuller et al, 2007;Priller et al, 2011). Recent studies have also shown that activation of the FGF (Emmenegger et al, 2013) and Wnt pathways (Anne et al, 2013) has tumour-supressing actions.…”

FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients

“…Increased expression of FoxM1 has been found in several human tumors suggesting a role in human carcinogenesis [13,[18][19][20][21][22][23][24][25][26][27]. Moreover, it has been shown that higher expression of FoxM1 was associated with poor prognosis of cancer patients and could serve as an independent predictor of poor survival in cancer [28][29][30][31][32][33][34]. Although much effort has been devoted to the investigation of FoxM1 function in cultured cells and animal systems, there are no definitive data to accurately predict long-term outcome in patients and to evaluate the prognostic value of FoxM1 in advanced NSCLC.…”