简介:尽管在理解癌症生物学方面取得了进展,恶性胶质瘤仍然无法治愈。本工作进行了一项多组学分析,以研究神经胶质瘤中氯化物细胞内通道1(CLIC1)的重要性。方法:覆盖转录组学的胶质瘤的多组学数据,基因组学,来自多个公共队列的DNA甲基化和单细胞转录组学被登记用于分析CLIC1。在CLIC1siRNA转染后,进行体外实验以测量U251和U373神经胶质瘤细胞中的凋亡和细胞迀移率。结果:CLIC1表达升高被证明可以稳定且独立地估计较差的生存结果。CLIC1表达在更晚期阶段更高,野生型IDH和未甲基化MGMT样品。在CLIC1上调的肿瘤中,致瘤性和抗癌免疫途径显着丰富。此外,CLIC1与癌症免疫周期呈正相关,基质激活,DNA损伤修复和细胞周期。抑制CLIC1导致神经胶质瘤细胞的凋亡和细胞运动减弱。在CLIC1上调的肿瘤中发现了更频繁的基因组改变。CLIC1表达与DNA甲基化呈显著负相关。CLIC1高表达样本对喜树碱较敏感,顺铂,阿霉素,厄洛替尼,紫杉醇,雷帕霉素,氯法拉滨,坦司匹霉素,甲氨蝶呤,依维莫司,TAK-733、曲美替尼和AZD8330。CLIC1上调的肿瘤表现出丰富的免疫细胞浸润,免疫检查点和调节剂的更高表达和类似的转录组分析,表明对免疫检查点阻断(ICB)的反应良好。然而,由于潮汐分数升高,具有CLIC1上调的肿瘤似乎对ICB有抗性。单细胞分析揭示了CLIC1在肿瘤细胞和肿瘤微环境中普遍表达。结论:总体而言,CLIC1是神经胶质瘤的一个有希望的治疗弱点。
Introduction: Despite advances in comprehending cancer biology, malignant gliomas remain incurable. The present work conducted a multi-omics analysis for investigating the significance of chloride intracellular channel 1 (CLIC1) in gliomas. Methods: Multi-omics data of glioma covering transcriptomics, genomics, DNA methylation and single-cell transcriptomics from multiple public cohorts were enrolled for analyzing CLIC1. In vitro experiments were conducted to measure apoptosis and cell mobility in U251 and U373 glioma cells following transfection of CLIC1 siRNAs. Results: Elevated CLIC1 expression was proven to stably and independently estimate worse survival outcomes. CLIC1 expression was higher in more advanced stage, wild-type IDH and unmethylated MGMT samples. Tumorigenic and anticancer immunity pathways were remarkably enriched in CLIC1-up-regulated tumors. Additionally, CLIC1 was positively linked with cancer-immunity cycle, stromal activation, DNA damage repair and cell cycle. Suppressing CLIC1 resulted in apoptosis and attenuated cell motility of glioma cells. More frequent genomic alterations were found in CLIC1-up-regulated tumors. CLIC1 expression presented a remarkably negative connection to DNA methylation. High CLIC1 expression samples were more sensitive to camptothecin, cisplatin, doxorubicin, erlotinib, paclitaxel, rapamycin, clofarabine, tanespimycin, methotrexate, everolimus, TAK-733, trametinib and AZD8330. Tumors with upregulated CLIC1 presented abundant immune cell infiltration, higher expression of immune-checkpoints and -modulators and similar transcriptome profiling, indicative of well response to immune-checkpoint blockade (ICB). Nevertheless, due to elevated TIDE score, tumors with CLIC1 upregulation appeared to be resistant to ICB. Single-cell analysis unveiled that CLIC1 was expressed ubiquitously in tumor cells and tumor microenvironment. Conclusions: Overall, CLIC1 was a promising treatment vulnerability in glioma.