文章：

室管膜瘤RELA融合亚组中的Notch通路：上调并与癌症干细胞标志物表达相关

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

原文发布日期：2019-07-16 

英文摘要：

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. 

摘要翻译： 

RELA融合型幕上室管膜瘤（ST-EPN）是一种预后不良的侵袭性亚型。基于Notch信号通路在RELA融合型室管膜瘤癌症干细胞（CSC）表型维持中的潜在作用，我们研究了该亚型中Notch通路及其靶基因的表达情况。我们同时评估了两种Notch抑制剂（DAPT和RO4929097）对RELA融合亚型室管膜瘤细胞系（BXD-1425）的细胞增殖、凋亡、克隆形成及CSCs标志物基因表达的影响，并基于GSE64415研究的大型临床数据集对Notch基因和CSCs标志物的生物信息学特征进行分析。研究发现，在幕上室管膜瘤各亚型中，Notch信号通路（NOTCH1、JAG1、JAG2和HES4）特异性在ST-EPN-RELA亚型中激活。Notch抑制剂处理RELA融合型室管膜瘤细胞系后，Notch信号表达受抑，但该通路在此背景下并非细胞增殖和存活的关键因素。ST-EPN中NOTCH1表达与CSCs标志物VEGFA和L1CAM过表达呈正相关，JAG1表达则与CCND1和CDK6过表达相关。此外，Notch抑制剂的体外处理诱导了CSCs标志物的下调表达。这些发现表明，Notch信号通路可能通过调控决定细胞表型与命运的基因表达，参与ST-EPN-RELA癌症干细胞的维持机制。

原文链接：

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