Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
CNS Neurosci Ther. 2020 Jul;26(7):741-753. doi: 10.1111/cns.13295. Epub 2020 Feb 16.
Patients with high-grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence. The outcome of HGG patients has improved little during the past decade. Therefore, molecular signatures are urgently needed for improving diagnosis, survival prediction and identification of therapeutic targets for HGG. E2F transcription factors (E2Fs), a family of transcription factors recognized as master regulators of cell proliferation, have been found to be involved in the pathogenesis of various tumor types.
To investigate the expression of E2Fs and their prognosis value in high-grade glioma (HGG).
Expression of E2Fs was analyzed in 394 HGG samples from TCGA dataset. E2Fs were generally expressed in HGG. Except for E2F3 and E2F5, expression of E2Fs was significantly upregulated and linked with grade progression. E2F1, E2F2, E2F7, and E2F8 were highly correlated with aggressive proliferation oncogenes, as well as potential therapeutic resistance oncogenes. Elevated E2Fs (not E2F3) were associated with adverse tumor features and poorer outcome. E2F7 and E2F8 exhibited superior outcome prediction performance compared with other E2Fs. Additionally, E2F7 and E2F8 independently predicted poorer survival in HGG patients. Gene set enrichment analysis identified a variety of critical oncogenic pathways that were tightly associated with E2F7 or E2F8, including epithelial-mesenchymal transition, NFκB, STAT3, angiogenesis pathways. Furthermore, elevated expression of E2F7 indicated worse therapeutic response of HGG to irradiation and silencing of E2F7 conferred higher cell-killing effect when combined with irradiation treatment. Mechanically, E2F7 directly regulates the transcriptional activity of EZH2 via binding at the corresponding promoter area.
E2Fs (except for E2F3 and E2F5) are highly expressed in HGG and indicate adverse outcome. E2F7 and E2F8 were identified as novel potential prognostic markers in HGG. E2F7 was further validated to be closely associated with radioresistance of HGG and a critical transcriptional regulator of EZH2.
由于内在或获得的治疗耐药性和难治性复发，患有高级别神经胶质瘤（HGG）的患者生存预后较差。在过去的十年中，HGG 患者的治疗效果几乎没有改善。因此，迫切需要分子特征来改善 HGG 的诊断、生存预测和治疗靶点的识别。E2F 转录因子（E2Fs）是一类被认为是细胞增殖的主要调节因子的转录因子家族，已被发现参与各种肿瘤类型的发病机制。
研究 E2F 在高级别神经胶质瘤（HGG）中的表达及其预后价值。
分析了 TCGA 数据集的 394 例 HGG 样本中的 E2Fs 表达。E2Fs 通常在 HGG 中表达。除了 E2F3 和 E2F5 之外，E2Fs 的表达显著上调，并与分级进展相关。E2F1、E2F2、E2F7 和 E2F8 与侵袭性增殖癌基因以及潜在的治疗耐药性癌基因高度相关。升高的 E2Fs（非 E2F3）与不良肿瘤特征和较差的预后相关。E2F7 和 E2F8 的预后预测性能优于其他 E2Fs。此外，E2F7 和 E2F8 独立预测 HGG 患者的生存率较低。基因集富集分析确定了与 E2F7 或 E2F8 紧密相关的多种关键致癌途径，包括上皮-间充质转化、NFκB、STAT3、血管生成途径。此外，E2F7 的高表达表明 HGG 对放疗的治疗反应较差，而 E2F7 的沉默与放疗联合治疗时赋予更高的细胞杀伤作用。在机制上，E2F7 通过结合相应的启动子区域直接调节 EZH2 的转录活性。
E2Fs（除了 E2F3 和 E2F5）在 HGG 中高表达，并提示预后不良。E2F7 和 E2F8 被确定为 HGG 中的新型潜在预后标志物。E2F7 进一步被验证与 HGG 的放射抵抗性密切相关，并且是 EZH2 的关键转录调节剂。
