PMID- 35982038
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20230119
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 8
DP  - 2022 Aug 18
TI  - FMRP modulates the Wnt signalling pathway in glioblastoma.
PG  - 719
LID - 10.1038/s41419-022-05019-w [doi]
LID - 719
AB  - 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/beta-Catenin and the 
      non-canonical WNT-ERK1/2 signalling pathways, reducing the stability of several 
      key transcription factors (i.e. beta-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.
CI  - (c) 2022. The Author(s).
FAU - Pedini, Giorgia
AU  - Pedini G
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy.
FAU - Buccarelli, Mariachiara
AU  - Buccarelli M
AD  - Department of Oncology and Molecular Medicine, Istituto Superiore di Sanita, 
      Rome, Italy.
FAU - Bianchi, Fabrizio
AU  - Bianchi F
AUID- ORCID: 0000-0001-7412-8638
AD  - Fondazione IRCCS Casa Sollievo della Sofferenza, Unit of Cancer Biomarkers, San 
      Giovanni Rotondo, Italy.
FAU - Pacini, Laura
AU  - Pacini L
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy.
AD  - UniCamillus, Saint Camillus International University of Health and Medical 
      Sciences, Rome, Italy.
FAU - Cencelli, Giulia
AU  - Cencelli G
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy.
FAU - D'Alessandris, Quintino Giorgio
AU  - D'Alessandris QG
AD  - Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS 
      - Universita Cattolica del Sacro Cuore, Rome, Italy.
FAU - Martini, Maurizio
AU  - Martini M
AD  - Department of Human & Childhood Pathology "G. Barresi", University of Messina 
      School of Medicine, Messina, Italy.
FAU - Giannetti, Stefano
AU  - Giannetti S
AD  - Department of Neuroscience, Institute of Anatomy, Universita Cattolica del Sacro 
      Cuore, Rome, Italy.
FAU - Sasso, Franceschina
AU  - Sasso F
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy.
FAU - Melocchi, Valentina
AU  - Melocchi V
AUID- ORCID: 0000-0001-9656-3681
AD  - Fondazione IRCCS Casa Sollievo della Sofferenza, Unit of Cancer Biomarkers, San 
      Giovanni Rotondo, Italy.
FAU - Farace, Maria Giulia
AU  - Farace MG
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy.
FAU - Achsel, Tilmann
AU  - Achsel T
AD  - Department of Fundamental Neurosciences (DNF), University of Lausanne, Lausanne, 
      Switzerland.
FAU - Larocca, Luigi M
AU  - Larocca LM
AUID- ORCID: 0000-0003-1739-4758
AD  - Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita 
      Cattolica del Sacro Cuore, Rome, Italy.
FAU - Ricci-Vitiani, Lucia
AU  - Ricci-Vitiani L
AD  - Department of Oncology and Molecular Medicine, Istituto Superiore di Sanita, 
      Rome, Italy. lriccivitiani@yahoo.it.
FAU - Pallini, Roberto
AU  - Pallini R
AD  - Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS 
      - Universita Cattolica del Sacro Cuore, Rome, Italy. roberto.pallini@unicatt.it.
FAU - Bagni, Claudia
AU  - Bagni C
AUID- ORCID: 0000-0002-4419-210X
AD  - Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, 
      Italy. claudia.bagni@unil.ch.
AD  - Department of Fundamental Neurosciences (DNF), University of Lausanne, Lausanne, 
      Switzerland. claudia.bagni@unil.ch.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220818
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (FMR1 protein, human)
RN  - 0 (Ribonucleoproteins)
RN  - 0 (beta Catenin)
RN  - 0 (messenger ribonucleoprotein)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
SB  - IM
MH  - Animals
MH  - *Brain Neoplasms/pathology
MH  - Cell Line, Tumor
MH  - Fragile X Mental Retardation Protein/*metabolism
MH  - *Glioblastoma/pathology
MH  - Humans
MH  - Mice
MH  - Neoplastic Stem Cells/metabolism
MH  - Ribonucleoproteins
MH  - Wnt Signaling Pathway/genetics
MH  - beta Catenin/metabolism
PMC - PMC9388540
COIS- The authors declare no competing interests.
EDAT- 2022/08/19 06:00
MHDA- 2022/08/23 06:00
PMCR- 2022/08/18
CRDT- 2022/08/18 23:14
PHST- 2022/02/25 00:00 [received]
PHST- 2022/06/10 00:00 [accepted]
PHST- 2022/06/06 00:00 [revised]
PHST- 2022/08/18 23:14 [entrez]
PHST- 2022/08/19 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/08/18 00:00 [pmc-release]
AID - 10.1038/s41419-022-05019-w [pii]
AID - 5019 [pii]
AID - 10.1038/s41419-022-05019-w [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Aug 18;13(8):719. doi: 10.1038/s41419-022-05019-w.