FOXP1inhibits cell growth and attenuates tumorigenicity of neuroblastoma

Abstract

BackgroundSegmental 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.MethodsMicroarray 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.ResultsLow 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-840) contains supplementary material, which is available to authorized users.

FOXP1 is a regulator of quiescence in healthy human CD4+ T cells and is constitutively repressed in T cells from patients with lymphoproliferative disorders

“…This is illustrated by genetic disruption of IKAROS, which was found to drive T‐cell transformation . The majority of published studies on FOXP1 in different tumor settings indicate that it acts as a tumor suppressor gene , namely in neuroblastoma , prostate cancer , non‐small cell lung cancer , endometrial cancer , ovarian and breast carcinoma , and in diffuse large B‐cell lymphoma (DLBCL). In the latter condition however, the shorter isoforms of FOXP1 act as oncogenes , and FOXP1 overexpression has actually been associated with a worse prognosis, similar to marginal zone lymphoma of MALT, another B cell malignancy .…”

Knockdown of LINC01614 inhibits lung adenocarcinoma cell progression by up‐regulating miR‐217 and down‐regulating FOXP1

“…For example, FOXP1 dysregulation is related to poor prognosis in B‐cell lymphomas and NSCLC . However, when it comes to other cancers like neuroblastoma or prostate cancer, FOXP1 can inhibit cell growth and attenuate tumorigenesis as a tumour suppressor . Hence, the role of FOXP1 in tumour progression is uncertain.…”

FOXP1 enhances tumor cell migration by repression of NFAT1 transcriptional activity in MDA‐MB‐231 cells

“…While nuclear expression was preponderantly discovered in tissues such as kidney, thyroid, cerebellum, tonsil, blood, and colon, cytoplasmic expression was found in tissues such as stomach, colon, and in cells such as lung macrophages (Banham et al, 2001). As for cancer, protein expression levels and compartmentalization of FOXP1 are also differed based on tissue and stages of cancer (Banham et al, 2001Fox et al, 2004;Giatromanolaki et al, 2006;Bates et al, 2008;Brown et al, 2008;Rayoo et al, 2009;Ackermann et al, 2014). So far, the effects of FOXP1 protein expression on the development of cancer has been only clarified by evaluating the correlation studies (Banham et al, 2001Fox et al, 2004;Bates et al, 2008;Brown et al, 2008;Rayoo et al, 2009;Ijichi et al, 2012;Zhou et al, 2014).…”