FMRP modulates the Wnt signalling pathway in glioblastoma.

Autor: Pedini G; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy., Buccarelli M; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy., Bianchi F; Fondazione IRCCS Casa Sollievo della Sofferenza, Unit of Cancer Biomarkers, San Giovanni Rotondo, Italy., Pacini L; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.; UniCamillus, Saint Camillus International University of Health and Medical Sciences, Rome, Italy., Cencelli G; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy., D'Alessandris QG; Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy., Martini M; Department of Human & Childhood Pathology 'G. Barresi', University of Messina School of Medicine, Messina, Italy., Giannetti S; Department of Neuroscience, Institute of Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy., Sasso F; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy., Melocchi V; Fondazione IRCCS Casa Sollievo della Sofferenza, Unit of Cancer Biomarkers, San Giovanni Rotondo, Italy., Farace MG; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy., Achsel T; Department of Fundamental Neurosciences (DNF), University of Lausanne, Lausanne, Switzerland., Larocca LM; Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy., Ricci-Vitiani L; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. lriccivitiani@yahoo.it., Pallini R; Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy. roberto.pallini@unicatt.it., Bagni C; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy. claudia.bagni@unil.ch.; Department of Fundamental Neurosciences (DNF), University of Lausanne, Lausanne, Switzerland. claudia.bagni@unil.ch.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Aug 18; Vol. 13 (8), pp. 719. Date of Electronic Publication: 2022 Aug 18.
DOI: 10.1038/s41419-022-05019-w
Abstrakt: Converging evidence indicates that the Fragile X Messenger Ribonucleoprotein (FMRP), which absent or mutated in Fragile X Syndrome (FXS), plays a role in many types of cancers. However, while FMRP roles in brain development and function have been extensively studied, its involvement in the biology of brain tumors remains largely unexplored. Here we show, in human glioblastoma (GBM) biopsies, that increased expression of FMRP directly correlates with a worse patient outcome. In contrast, reductions in FMRP correlate with a diminished tumor growth and proliferation of human GBM stem-like cells (GSCs) in vitro in a cell culture model and in vivo in mouse brain GSC xenografts. Consistently, increased FMRP levels promote GSC proliferation. To characterize the mechanism(s) by which FMRP regulates GSC proliferation, we performed GSC transcriptome analyses in GSCs expressing high levels of FMRP, and in these GSCs after knockdown of FMRP. We show that the WNT signalling is the most significantly enriched among the published FMRP target genes and genes involved in ASD. Consistently, we find that reductions in FMRP downregulate both the canonical WNT/β-Catenin and the non-canonical WNT-ERK1/2 signalling pathways, reducing the stability of several key transcription factors (i.e. β-Catenin, CREB and ETS1) previously implicated in the modulation of malignant features of glioma cells. Our findings support a key role for FMRP in GBM cancer progression, acting via regulation of WNT signalling.
(© 2022. The Author(s).)
Databáze: MEDLINE
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