Sialidase NEU4 is involved in glioblastoma stem cell survival

I. Silvestri, F. Testa, R. Zappasodi, C. W. Cairo, Y. Zhang, B. Lupo, R. Galli, M. Di Nicola, B. Venerando, C. Tringali

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The human sialidase, NEU4, has emerged as a possible regulator of neuronal differentiation and its overexpression has been demonstrated to promote the acquisition of a stem cell-like phenotype in neuroblastoma cells. In this paper, we demonstrated that glioblastoma stem cells (GSCs) isolated from glioblastoma multiforme (GBM) cell lines and patients' specimens as neurospheres are specifically marked by the upregulation of NEU4; in contrast, the expression of NEU4 is very low in non-neurosphere-differentiated GBM cells. We showed that NEU4 silencing by miRNA or a chemical inhibitor of its catalytic activity triggered key events in GSCs, including (a) the activation of the glycogen synthase kinase 3β, with the consequent inhibition of Sonic Hedgehog and Wnt/β-catenin signalling pathways; (b) the decrease of the stem cell-like gene expression and marker signatures, evidenced by the reduction of NANOG, OCT-4, SOX-2, CD133 expression, ganglioside GD3 synthesis, and an altered protein glycosylation profile; and (c) a significant decrease in GSCs survival. Consistent with this finding, increased NEU4 activity and expression induced in the more differentiated GBM cells by the NEU4 agonist thymoquinone increased the expression of OCT-4 and GLI-1. Thus, NEU4 expression and activity appeared to help to determine the molecular signature of GSCs and to be closely connected with their survival properties. Given the pivotal role played by GSCs in GBM lethality, our results strongly suggest that NEU4 inhibition could significantly improve current therapies against this tumour.

Original languageEnglish
Article numbere1381
JournalCell Death and Disease
Volume5
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Neuraminidase
Glioblastoma
Cell Survival
Stem Cells
Glycogen Synthase Kinase 3
Catenins
Wnt Signaling Pathway
MicroRNAs
Neuroblastoma
Glycosylation
Transcriptome
Up-Regulation
Phenotype
Cell Line
Survival

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Silvestri, I., Testa, F., Zappasodi, R., Cairo, C. W., Zhang, Y., Lupo, B., ... Tringali, C. (2014). Sialidase NEU4 is involved in glioblastoma stem cell survival. Cell Death and Disease, 5(8), [e1381]. https://doi.org/10.1038/cddis.2014.349

Sialidase NEU4 is involved in glioblastoma stem cell survival. / Silvestri, I.; Testa, F.; Zappasodi, R.; Cairo, C. W.; Zhang, Y.; Lupo, B.; Galli, R.; Di Nicola, M.; Venerando, B.; Tringali, C.

In: Cell Death and Disease, Vol. 5, No. 8, e1381, 2014.

Research output: Contribution to journalArticle

Silvestri, I, Testa, F, Zappasodi, R, Cairo, CW, Zhang, Y, Lupo, B, Galli, R, Di Nicola, M, Venerando, B & Tringali, C 2014, 'Sialidase NEU4 is involved in glioblastoma stem cell survival', Cell Death and Disease, vol. 5, no. 8, e1381. https://doi.org/10.1038/cddis.2014.349
Silvestri, I. ; Testa, F. ; Zappasodi, R. ; Cairo, C. W. ; Zhang, Y. ; Lupo, B. ; Galli, R. ; Di Nicola, M. ; Venerando, B. ; Tringali, C. / Sialidase NEU4 is involved in glioblastoma stem cell survival. In: Cell Death and Disease. 2014 ; Vol. 5, No. 8.
@article{b6d202f3f76f4a09840989c65185bba0,
title = "Sialidase NEU4 is involved in glioblastoma stem cell survival",
abstract = "The human sialidase, NEU4, has emerged as a possible regulator of neuronal differentiation and its overexpression has been demonstrated to promote the acquisition of a stem cell-like phenotype in neuroblastoma cells. In this paper, we demonstrated that glioblastoma stem cells (GSCs) isolated from glioblastoma multiforme (GBM) cell lines and patients' specimens as neurospheres are specifically marked by the upregulation of NEU4; in contrast, the expression of NEU4 is very low in non-neurosphere-differentiated GBM cells. We showed that NEU4 silencing by miRNA or a chemical inhibitor of its catalytic activity triggered key events in GSCs, including (a) the activation of the glycogen synthase kinase 3β, with the consequent inhibition of Sonic Hedgehog and Wnt/β-catenin signalling pathways; (b) the decrease of the stem cell-like gene expression and marker signatures, evidenced by the reduction of NANOG, OCT-4, SOX-2, CD133 expression, ganglioside GD3 synthesis, and an altered protein glycosylation profile; and (c) a significant decrease in GSCs survival. Consistent with this finding, increased NEU4 activity and expression induced in the more differentiated GBM cells by the NEU4 agonist thymoquinone increased the expression of OCT-4 and GLI-1. Thus, NEU4 expression and activity appeared to help to determine the molecular signature of GSCs and to be closely connected with their survival properties. Given the pivotal role played by GSCs in GBM lethality, our results strongly suggest that NEU4 inhibition could significantly improve current therapies against this tumour.",
author = "I. Silvestri and F. Testa and R. Zappasodi and Cairo, {C. W.} and Y. Zhang and B. Lupo and R. Galli and {Di Nicola}, M. and B. Venerando and C. Tringali",
year = "2014",
doi = "10.1038/cddis.2014.349",
language = "English",
volume = "5",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Sialidase NEU4 is involved in glioblastoma stem cell survival

AU - Silvestri, I.

AU - Testa, F.

AU - Zappasodi, R.

AU - Cairo, C. W.

AU - Zhang, Y.

AU - Lupo, B.

AU - Galli, R.

AU - Di Nicola, M.

AU - Venerando, B.

AU - Tringali, C.

PY - 2014

Y1 - 2014

N2 - The human sialidase, NEU4, has emerged as a possible regulator of neuronal differentiation and its overexpression has been demonstrated to promote the acquisition of a stem cell-like phenotype in neuroblastoma cells. In this paper, we demonstrated that glioblastoma stem cells (GSCs) isolated from glioblastoma multiforme (GBM) cell lines and patients' specimens as neurospheres are specifically marked by the upregulation of NEU4; in contrast, the expression of NEU4 is very low in non-neurosphere-differentiated GBM cells. We showed that NEU4 silencing by miRNA or a chemical inhibitor of its catalytic activity triggered key events in GSCs, including (a) the activation of the glycogen synthase kinase 3β, with the consequent inhibition of Sonic Hedgehog and Wnt/β-catenin signalling pathways; (b) the decrease of the stem cell-like gene expression and marker signatures, evidenced by the reduction of NANOG, OCT-4, SOX-2, CD133 expression, ganglioside GD3 synthesis, and an altered protein glycosylation profile; and (c) a significant decrease in GSCs survival. Consistent with this finding, increased NEU4 activity and expression induced in the more differentiated GBM cells by the NEU4 agonist thymoquinone increased the expression of OCT-4 and GLI-1. Thus, NEU4 expression and activity appeared to help to determine the molecular signature of GSCs and to be closely connected with their survival properties. Given the pivotal role played by GSCs in GBM lethality, our results strongly suggest that NEU4 inhibition could significantly improve current therapies against this tumour.

AB - The human sialidase, NEU4, has emerged as a possible regulator of neuronal differentiation and its overexpression has been demonstrated to promote the acquisition of a stem cell-like phenotype in neuroblastoma cells. In this paper, we demonstrated that glioblastoma stem cells (GSCs) isolated from glioblastoma multiforme (GBM) cell lines and patients' specimens as neurospheres are specifically marked by the upregulation of NEU4; in contrast, the expression of NEU4 is very low in non-neurosphere-differentiated GBM cells. We showed that NEU4 silencing by miRNA or a chemical inhibitor of its catalytic activity triggered key events in GSCs, including (a) the activation of the glycogen synthase kinase 3β, with the consequent inhibition of Sonic Hedgehog and Wnt/β-catenin signalling pathways; (b) the decrease of the stem cell-like gene expression and marker signatures, evidenced by the reduction of NANOG, OCT-4, SOX-2, CD133 expression, ganglioside GD3 synthesis, and an altered protein glycosylation profile; and (c) a significant decrease in GSCs survival. Consistent with this finding, increased NEU4 activity and expression induced in the more differentiated GBM cells by the NEU4 agonist thymoquinone increased the expression of OCT-4 and GLI-1. Thus, NEU4 expression and activity appeared to help to determine the molecular signature of GSCs and to be closely connected with their survival properties. Given the pivotal role played by GSCs in GBM lethality, our results strongly suggest that NEU4 inhibition could significantly improve current therapies against this tumour.

UR - http://www.scopus.com/inward/record.url?scp=84906880198&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906880198&partnerID=8YFLogxK

U2 - 10.1038/cddis.2014.349

DO - 10.1038/cddis.2014.349

M3 - Article

AN - SCOPUS:84906880198

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 8

M1 - e1381

ER -