c-myc/XTP6/NDH2/NF-κB 正反馈环促进胶质母细胞瘤的恶性进展。

Positive feedback loop of c-myc/XTP6/NDH2/NF-κB to promote malignant progression in glioblastoma.

机构信息

Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.

Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Nanchang University, Nanchang, Jiangxi, 330006, China.

出版信息

J Exp Clin Cancer Res. 2024 Jul 5;43(1):187. doi: 10.1186/s13046-024-03109-5.

DOI:10.1186/s13046-024-03109-5

PMID:38965580

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11225266/

Abstract

BACKGROUND

Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored.

METHODS

Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play.

RESULTS

XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo.

CONCLUSION

The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

摘要

背景

最近的研究强调了 NF-κB 信号通路在癌症的发生和发展中的重要作用。此外，长非编码 RNA（lncRNA）已被确定为维持 NF-κB 信号通路功能的关键调节因子。尽管有这些发现，但 lncRNA 影响 NF-κB 途径的潜在分子机制在很大程度上仍未得到探索。

方法

利用生物信息学分析方法研究 XTP6 的差异表达和预后意义。通过体外和体内实验进一步阐明 XTP6 的功能作用。为了估计 XTP6 和 NDH2 之间的相互作用，进行了 RNA 下拉和 RNA 免疫沉淀（RIP）实验。使用 RNA 纯化的染色质分离（ChIRP）实验研究 XTP6 与 IκBα 启动子之间的连接。此外，进行染色质免疫沉淀（ChIP）实验分析 c-myc 与 XTP6 启动子的结合亲和力，深入了解发挥作用的调节机制。

结果

XTP6 在多形性胶质母细胞瘤（GBM）组织中显著上调，并与 GBM 患者的不良预后相关。我们的研究表明，XTP6 可以促进 GBM 的体外和体内恶性进展。此外，XTP6 通过将 NDH2 募集到 IκBα 启动子来下调 IκBα 的表达，导致 H3K27me3 水平升高，从而降低 IκBα 的转录活性。此外，GBM 的进展进一步由 c-myc 介导的 XTP6 上调驱动，与 IκBα 建立正反馈环，使 NF-κB 信号通路的持续激活得以维持。值得注意的是，应用针对 NF-κB 信号通路的抑制剂可有效抑制 XTP6 诱导的持续激活，导致体内肿瘤形成显著减少。