FOXP3, a novel glioblastoma oncosuppressor, affects proliferation and migration

Abstract

// Véronique Frattini 1,3 , Federica Pisati 1,3 , Maria Carmela Speranza 1,3 , Pietro Luigi Poliani 4 , Gianmaria Frigé 3 , Gabriele Cantini 1,3 , Dimos Kapetis 2 , Manuela Cominelli 4 , Alessandra Rossi 1,3 , Gaetano Finocchiaro 1,3 and Serena Pellegatta 1,3 1 Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milan, Italy 2 Service of Bioinformatics, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milan, Italy 3 Department of Experimental Oncology, European Institute of Oncology - Campus IFOM-IEO, Milan, Italy 4 Department of Pathology, University of Brescia, Brescia, Italy Correspondence: Serena Pellegatta, email: // Gaetano Finocchiaro, email: // Keywords : FOXP3, glioblastoma, neurospheres, proliferation, migration Received : September 03, 2012, Accepted : September 20, 2012, Published : September 22, 2012 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.