FOXP1 inhibits cell growth and attenuates tumorigenicity of neuroblastoma

BMC Cancer

Sandra Ackermann²  Hayriye Kocak²  Barbara Hero²  Volker Ehemann³  Yvonne Kahlert²  André Oberthuer²  Frederik Roels²  Jessica Theißen²  Margarete Odenthal¹  Frank Berthold²  Matthias Fischer² 

[1] Institute of Pathology, University of Cologne, Cologne 50924, Germany

[2] Department of Pediatric Oncology and Hematology and Center for Molecular Medicine Cologne (CMMC), Children’s Hospital, University of Cologne, Kerpener Straße 62, Cologne 50924, Germany

[3] Institute of Pathology (INF 220), University of Heidelberg, Heidelberg 69120, Germany

关键词: Disease progression;    Cell proliferation;    Tumor suppressor;    Neuroblastoma;    FoxP1;   

Others  :  1118219
DOI  :  10.1186/1471-2407-14-840

 received in 2014-06-03, accepted in 2014-10-30,  发布年份 2014

【 摘 要 】

Background

Segmental genomic copy number alterations, such as loss of 11q or 3p and gain of 17q, are well established markers of poor outcome in neuroblastoma, and have been suggested to comprise tumor suppressor genes or oncogenes, respectively. The gene forkhead box P1 (FOXP1) maps to chromosome 3p14.1, a tumor suppressor locus deleted in many human cancers including neuroblastoma. FoxP1 belongs to a family of winged-helix transcription factors that are involved in processes of cellular proliferation, differentiation and neoplastic transformation.

Methods

Microarray expression profiles of 476 neuroblastoma specimens were generated and genes differentially expressed between favorable and unfavorable neuroblastoma were identified. FOXP1 expression was correlated to clinical markers and patient outcome. To determine whether hypermethylation is involved in silencing of FOXP1, methylation analysis of the 5′ region of FOXP1 in 47 neuroblastomas was performed. Furthermore, FOXP1 was re-expressed in three neuroblastoma cell lines to study the effect of FOXP1 on growth characteristics of neuroblastoma cells.

Results

Low expression of FOXP1 is associated with markers of unfavorable prognosis like stage 4, age >18 months and MYCN amplification and unfavorable gene expression-based classification (P < 0.001 each). Moreover, FOXP1 expression predicts patient outcome accurately and independently from well-established prognostic markers. Array-based CGH analysis of 159 neuroblastomas revealed that heterozygous loss of the FOXP1 locus was a rare event (n = 4), but if present, was associated with low FOXP1 expression. By contrast, DNA methylation analysis in 47 neuroblastomas indicated that hypermethylation is not regularly involved in FOXP1 gene silencing. Re-expression of FoxP1 significantly impaired cell proliferation, viability and colony formation in soft agar. Furthermore, induction of FOXP1 expression led to cell cycle arrest and apoptotic cell death of neuroblastoma cells.

Conclusions

Our results suggest that down-regulation of FOXP1 expression is a common event in high-risk neuroblastoma pathogenesis and may contribute to tumor progression and unfavorable patient outcome.

【 授权许可】

   
2014 Ackermann et al.; licensee BioMed Central Ltd.

【 图 表 】

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