RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
钙联蛋白在胶质瘤恶性进展和肿瘤微环境中的双重作用
英文原题：The dual role of calnexin on malignant progression and tumor microenvironment in glioma.
查看英文原题
The dual role of calnexin on malignant progression and tumor microenvironment in glioma.
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中文摘要
胶质瘤是最常见的恶性脑肿瘤。既往研究报道，钙联蛋白（CANX）在包括胶质瘤在内的多种恶性肿瘤中显著上调，但其在胶质瘤中的生物学功能和机制仍不清楚。
本研究通过基于液相色谱-串联质谱的蛋白质组学和生物信息学分析，鉴定了3例原发性多形性胶质母细胞瘤（GBM）组织和3例癌旁组织中的差异表达蛋白。通过CCK-8实验、Matrigel侵袭实验、划痕愈合实验、流式细胞术等在胶质瘤细胞系（T98G和A172）中研究了CANX的生物学功能和分子机制。采用生物信息学方法分析TCGA数据库中胶质瘤患者的免疫微环境，并分析GEO数据库中8例未经治疗的原发性GBM的单细胞测序数据。蛋白质组学分析发现，与癌旁组织相比，CANX在胶质瘤组织中显著过表达。TCGA数据验证了这一结果，并显示CANX与患者不良预后相关。细胞水平的一系列实验发现，CANX过表达显著增强了GBM细胞的增殖、迁移和侵袭能力，而CANX沉默则具有相反效应。
进一步研究发现，这一效应可能通过激活PI3K/AKT/mTOR信号通路介导。此外，免疫浸润分析发现，CANX高表达胶质瘤组织中CD8+ T细胞、NK 细胞和肥大细胞较少，同时肿瘤纯度显著降低，免疫检查点表达显著升高。单细胞测序数据分析表明，CANX主要表达于星形胶质细胞和树突状细胞。
总之，本研究提示CANX可能通过PI3K/AKT/mTOR信号通路促进胶质瘤的恶性进展，并在胶质瘤免疫逃逸中发挥重要作用。因此，CANX可能是胶质瘤一个有价值的治疗靶点。
展开英文摘要原文
Glioma is the most common malignant brain tumor. Previous studies have reported that calnexin (CANX) is significantly up-regulated in a variety of malignant tumors, including glioma, but its biological function and mechanism in glioma is still unclear. In this study, differentially expressed proteins in 3 primary glioblastoma multiforme (GBM) tissues and 3 paracancer tissues were identified by liquid chromatography-tandem mass spectrometry-based proteomic and bioinformatic analysis. The biological function and molecular mechanism of CANX were studied in glioma cell lines (T98G and A172) by CCK-8 assay, matrigel invasion assay, wound healing assay, flow cytometry and so on.
Bioinformatics methods were used to analyze the immune microenvironment of glioma patients in TCGA database, and single cell sequencing data of 8 cases of untreated primary GBM in GEO database were analyzed. Proteomic analysis found that CANX was significantly overexpressed in glioma tissues comparing with paracancer tissues.
The data from TCGA validated this result and showed that CANX was associated with poor prognosis of patients. A series of experiments at the cellular level found that CANX overexpression significantly enhanced the proliferation, migration and invasion ability of GBM cells, whereas CANX silencing had opposite effects.
Further research found this effect may be mediated through the activation of the PI3K/AKT/mTOR signaling.
In addition, immune infiltration analysis found that CANX high-expression glioma tissues exhibited fewer CD8 + T cells, natural killer cells and mast cells, along with significantly decreased tumor purity and significantly increased immune checkpoints expression. Single cell sequencing data analysis indicated that CANX was primarily expressed in astrocytes and dendritic cells.
In conclusion, this study suggested that CANX may promote the malignant progression of glioma through PI3K/AKT/mTOR signaling pathway and play an important role in glioma immune escape.
Therefore, CANX may be a valuable therapeutic target for glioma.
论文信息
- 作者
- Wang W、Shi Y、Yan B、Cai Y、Zheng H、Zhang Y、Wang L、Wang H
- 第一作者单位
- National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.China
- 通讯作者单位
- National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China. whj@nwu.edu.cn.China
- 期刊
- Scientific reports2024 Dec 28
- 原文标识
- PubMed 39730581 · DOI 10.1038/s41598-024-81192-6
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