title: FOXP3, a novel glioblastoma oncosuppressor, affects proliferation and migration.
abstract: The transcription factor FOXP3 plays an essential role in regulatory T cell development and function. In addition, it has recently been identified as a tumor suppressor in different cancers. Here, we report that FOXP3 is expressed in normal brain but strongly down-regulated in glioblastoma (GB) and in corresponding GB stem-like cells growing in culture as neurospheres (GB-NS), as evaluated by real time-PCR and confirmed by immunohistochemistry on an independent set of GB. FOXP3 expression was higher in low-grade gliomas than in GB. Interestingly, we also found that neurosphere generation, a feature present in 58% of the GB that we examined, correlated with lower expression of FOXP3 and shorter patient survival. FOXP3 silencing in one GB-NS expressing measurable levels of the gene caused a significant increase in proliferation and migration as well as highly aggressive growth in xenografts. Conversely, FOXP3 over-expression impaired GB-NS migration and proliferation in vitro. We also demonstrated using ChiP that FOXP3 is a transcriptional regulator of p21 and c-MYC supporting the idea that dysregulated expression of these factors is a major mechanism of tumorigenesis driven by the loss of FOXP3 expression in gliomas. These findings support the assertion that FOXP3 exhibits tumor suppressor activity in glioblastomas.
authors.affiliation: Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Véronique
authors.initials: V
authors.lastname: Frattini
authors.forename: Federica
authors.initials: F
authors.lastname: Pisati
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Speranza
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Frigé
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cantini
authors.forename: Dimos
authors.initials: D
authors.lastname: Kapetis
authors.forename: Manuela
authors.initials: M
authors.lastname: Cominelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rossi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016271:Proto-Oncogene Proteins c-myc
keywords: FOXP3; glioblastoma; migration; neurospheres; proliferation