Please use this identifier to cite or link to this item:
Title: Controllo del self-renewal e della tumorigenicità delle glioblastoma “stem-like” cells ad opera di FOXG1
Other Titles: Regulation of Glioblastoma Stem-Like Cell Self-Renewal and Tumorigenicity by the Transcription Factor FOXG1
Authors: Perin, Alessandro
Supervisore/Tutore: Leanza, Giampiero
Cosupervisore: Stifani, Stefano
Issue Date: 17-Apr-2012
Publisher: Università degli studi di Trieste
Glioblastoma (GBM) is the most common and malignant primary brain tumour. GBM prognosis remains dismal despite available treatments, be- cause of tumour recurrence. According to the "Glioma Stem-like Cell" (GSC) hypothesis, GBM recurrence is sustained by a fraction of cells that share similarities with normal Neural Stem Cells / Neural Precursors (NSCs). In potential agreement with this possibility, primary cell cultures with characteristics of GSCs can be established from GBM. These cells display typical hallmarks of NSCs, namely unlimited self-renewal and ability to differentiate into different neural lineages in vitro. Most importantly, GSCs are highly tumorigenic when transplanted intracranially in vivo and their in vitro self-renewal potential correlates positively with tumorigenicity and negatively with prognosis in Glioma patients. We hypothesize that the tumour-forming potential of GSCs may result from the deregulation of molecular mechanisms normally involved in NSC self-renewal, proliferation and/or differentiation. In this regard, the fork-head transcription factor, FOXG1, promotes the self-renewal of both embryonic and adult NSCs. Here we show that FOXG1 mRNA and protein are up-regulated in human Gliomas and that elevated FOXG1 expression is a bad prognostic factor in GBM patients. We show further that FOXG1 is expressed in a sub-population of GBM cells with NSC-like characteristics, as well as in cultured GSCs. More importantly, knockdown of FOXG1 significantly decreases GSC self-renewal, with a concomitant increase of the cell-cycle inhibitor, p21Cip1. We also show that FOXG1 is co-expressed in GBM and GSCs with the transcriptional co-repressor TLE, a protein known to work together with FOXG1 during forebrain development. The effect of FOXG1 knockdown on GSC self-renewal is phenocopied by TLE knockdown, as well as by the forced over-expression of the previously characterized TLE:FOXG1 antagonist, GRG6, a protein with little or no expression in GBM. More importantly, mouse orthotopic implantations of human GSCs, which were either silenced for FOXG1 or over-expressing GRG6, gave rise to smaller tumours when compared to control condition; this tumor size reduction resulted in prolonged mice survival. Together, these results suggest that FOXG1 and TLE are important regulators of GBM tumorigenesis.
Ciclo di dottorato: XXIV Ciclo
Keywords: GlioblastomaNeurogenesisGroucho/TLEGlioblastoma "Stem-like" CellsSelf-renewal
Type: Doctoral
Language: it
Settore scientifico-disciplinare: BIO/09 FISIOLOGIA
NBN: urn:nbn:it:units-9192
Appears in Collections:Scienze mediche

Files in This Item:
File Description SizeFormat Existing users please Login
perin_phd.pdfTesi PhD1.57 MBAdobe PDF    Request a copy
Show full item record

CORE Recommender

Page view(s) 20

Last Week
Last month
checked on Nov 29, 2020


checked on Nov 29, 2020

Google ScholarTM


This item is licensed under a Creative Commons License Creative Commons