FOXG1 dysregulation is a frequent event in medulloblastoma

Abstract

Medulloblastomas represent 20% of malignant brain tumors of childhood. Although, they show multiple, non-random genomic alterations, no common, early genetic event involving all histologic types of medulloblastomas have been described. Nineteen medulloblastomas were analyzed using chromosomal comparative genomic hybridization (cCGH). Nine tumors with the most frequent number of genetic changes were further analyzed using bacterial artificial chromosome array CGH (aCGH). With aCGH, the frequency of gains and losses were higher than with cCGH. Chromosome 2p gains spanning 2p11-2p25 including N-myc locus, 2p24.1 were detected in 5/9 (55%) tumors while 14q12 gains were detected in 6/9 (67%) tumors. The 14q12 locus overlapped with the FOXGI gene locus. Quantitative real time PCR showed a 2-7-fold copy gain for FOXG1 in all the nine tumors. Protein expression was demonstrated by immunohistochemistry in all histologic types. The expression of FOXG1 and p21cip1 showed an inverse relationship. FOXG1 copy gain (>2 to 21 folds) was seen in 93% (55/59) of a validating set of tumors and showed a positive correlation with protein expression (Spearman's rank order correlation coefficient = 0.276; P = 0.038) representing the first report of FOXG1 dysregulation in medulloblastoma. Modulation of FOXG1 expression in DAOY cell line using siRNA showed a modest decrease in proliferation with a 2-fold upregulation of p21cip1. Current reports indicate that FOXG1 represses TGF-beta induced expression of p21cip1 and cytostasis, and forms a transcriptional repressor complex with Notch signaling induced hes1. Our findings are consistent with a role for FOXG1 in the inhibition of TGF-beta induced cytostasis in medulloblastoma.

A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization

“…In this study, we showed that overexpression of FOXG1 in neuroblastoma cells reduces CDKN1A expression. This inhibitory role of FoxG1 on TGFβ-induced CDKN1A expression has already been described in earlier reports [Adesina et al 2007;Chan et al 2009]. The p.R244C FoxG1 mutant loses its effect, suggesting that this mutation affects the expression of CDKN1A at the transcriptional level in SH-SY5Y cells.…”

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

“…This promalignant function of NCAM1 is mediated by its interaction with fibroblast growth factor receptor (38,48). FOXG1 acts as an oncoprotein inhibiting TGF-b-mediated antiproliferative responses in medulloblastomas and ovarian cancer cells through suppressing p21 WAF1/CIP1 transcription (37,49). Integrins are the most important matrix receptors and their downregulation can promote dissemination of primary tumor but also suppress the attachment of already migrating tumor cells at distant sites.…”

Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis

“…Moreover, neither beneficial effects of these manipulations require irreversible transgene activation (Figs. 5, 7), especially biohazardous in the case of Foxg1 [68,69], nor do these manipulations induce any transformation foci (data not shown), so making them even more appealing for therapeutic approaches. Hopefully, delivering these treatments by molecular tools different from lentivectors, besides preventing genotoxicity of multiple insertional mutations [70], will fully unveil the neuronogenic potential of such manipulations (Figs.…”