Notch pathway in ependymoma RELA-fused subgroup: upregulation and association with cancer stem cells markers expression

• Published in: Cancer gene therapy Vol. 27; no. 6; pp. 509 - 512
• Main Authors: de Almeida Magalhães, Taciani, Cruzeiro, Gustavo Alencastro Veiga, de Sousa, Graziella Ribeiro, da Silva, Keteryne Rodrigues, Lira, Régia Caroline Peixoto, Scrideli, Carlos Alberto, Tone, Luiz Gonzaga, Valera, Elvis Terci, Borges, Kleiton Silva
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2020; Nature Publishing Group
• Subjects: 13/106; 13/2; 13/31; 13/95; 38/1; 38/39; 38/77; 631/67/1922; 631/67/2332; 692/53; Apoptosis; Biomedical and Life Sciences; Biomedicine; Brief Communication; Cell fate; Cell growth; Cell proliferation; Cell survival; Diagnosis; Gene Expression; Gene Therapy; Genetic aspects; Genetic markers; Gliomas; Health aspects; Medical prognosis; Notch1 protein; Phenotypes; RelA protein; Signal transduction; Stem cells; Brazil
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-019-0122-x

RELA
-fused supratentorial (ST) ependymoma (EPN) is an aggressive subgroup with poor prognosis. Considering the putative role of Notch signaling in the maintenance of the cancer stem cells (CSC) phenotype in RELA-fused EPN, we investigated the expression of Notch pathway and its target genes in this subgroup. We also evaluated the effects of two Notch inhibitors (DAPT and RO4929097) on cell proliferation, apoptosis, colony formation, and CSCs markers gene expression on EPN cell line of the RELA-fused subgroup (BXD-1425). In addition, in silico signatures of the Notch genes and CSCs markers were analyzed on a large clinical dataset from GSE64415 study. We found that among the ST-EPN subgroups the Notch signaling (
NOTCH1
,
JAG1
,
JAG2
, and
HES4
) is specifically activated in the ST-EPN-RELA. Furthermore, treatment of the RELA-fused EPN cell line with the Notch inhibitors impaired the Notch signaling expression and revealed that Notch axis is not essential for cell proliferation and survival in this setting.
NOTCH1
expression in ST-EPN was correlated with the CSCs markers
VEGFA
and
L1CAM
overexpression and
JAG1
expression was correlated with the
CCND1
and
CDK6
overexpression. In addition, in vitro treatment with Notch inhibitors induced downregulation of CSCs markers. These findings indicate that Notch signaling can be involved in the ST-EPN-RELA CSCs maintenance by modulating the expression of genes responsible for cell phenotype and cell fate.