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泛素-蛋白酶体系统介导的泛素化修饰模式及低级别胶质瘤肿瘤微环境浸润、干性和细胞衰老特征。

Ubiquitin-proteasome system-mediated ubiquitination modification patterns and characterization of tumor microenvironment infiltration, stemness and cellular senescence in low-grade glioma.

机构信息

The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.

出版信息

Aging (Albany NY). 2023 Apr 11;15(8):2970-2998. doi: 10.18632/aging.204650.


DOI:10.18632/aging.204650
PMID:37053008
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10188348/
Abstract

The Ubiquitin-proteasome system (UPS) performs a crucial role in immune activation and tumorigenesis. Nevertheless, the comprehensive role of the ubiquitin-proteasome system in the low-grade glioma (LGG) tumor microenvironment (TME) remains unknown. Ubiquitination modification patterns in LGG patients and corresponding characteristics of tumor immune traits, CSC stemness, and cellular senescence were evaluated via a comprehensive analysis of 20 ubiquitination modification regulators. For quantification of the ubiquitination modification status of individual patients, the UM-score was constructed and associated with TME characteristics, clinical features, cancer stem cell stemness, cellular senescence, prognosis, and immunotherapy efficacy. We identified that alterations in multiple ubiquitination regulators are linked to patient survival and the shaping of the tumor microenvironment. We found two different styles of ubiquitination modification in patients with low-grade glioma (immune-inflamed differentiation and immune-exclude dedifferentiation), characterized by high and low UM-score, and the two regulatory patterns of ubiquitination modification on immunity, stemness feature, and cellular senescence. We demonstrate that the UM-score could forecast the subtype of LGG, the immunologic infiltration traits, the biological process, the stemness feature, and the cellular senescence trait. Notably, the UM-score was related to immunotherapeutic efficacy, implying that modifying ubiquitination modification patterns by targeting ubiquitination modification regulators or ubiquitination modification pattern signature genes to reverse unfavorable TME properties will provide new insights into cancer immunotherapy. This research indicated that the ubiquitin-proteasome system is crucial in the formation of TME complexity and multiformity. The UM-score can determine ubiquitination modification status in individual patients, bringing about more personalized and effective immunotherapeutic tactics.

摘要

泛素-蛋白酶体系统(UPS)在免疫激活和肿瘤发生中起着至关重要的作用。然而,泛素-蛋白酶体系统在低级别神经胶质瘤(LGG)肿瘤微环境(TME)中的全面作用仍不清楚。通过对 20 种泛素化修饰调节剂的综合分析,评估了 LGG 患者的泛素化修饰模式及其对应肿瘤免疫特征、CSC 干性和细胞衰老的特征。为了定量分析个体患者的泛素化修饰状态,构建了 UM 评分,并将其与 TME 特征、临床特征、癌症干细胞干性、细胞衰老、预后和免疫治疗疗效相关联。我们发现,多个泛素化调节剂的改变与患者的生存和肿瘤微环境的形成有关。我们发现,低级别神经胶质瘤患者存在两种不同的泛素化修饰方式(免疫炎症分化和免疫排斥去分化),表现为高和低 UM 评分,以及两种不同的泛素化修饰对免疫、干性特征和细胞衰老的调节模式。我们证明,UM 评分可以预测 LGG 的亚型、免疫浸润特征、生物学过程、干性特征和细胞衰老特征。值得注意的是,UM 评分与免疫治疗疗效相关,这意味着通过靶向泛素化修饰调节剂或泛素化修饰模式特征基因来改变不利的 TME 特性,将为癌症免疫治疗提供新的思路。这项研究表明,泛素-蛋白酶体系统在 TME 复杂性和多样性的形成中起着关键作用。UM 评分可以确定个体患者的泛素化修饰状态,带来更个性化和有效的免疫治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/84f270b1497f/aging-15-204650-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/fa02f290ce02/aging-15-204650-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/4a9595bd3bf8/aging-15-204650-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/1b7616645498/aging-15-204650-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/5a0aaf477042/aging-15-204650-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/8fd9cfe78ad4/aging-15-204650-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/84f270b1497f/aging-15-204650-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/fa02f290ce02/aging-15-204650-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/4a9595bd3bf8/aging-15-204650-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/1b7616645498/aging-15-204650-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/5a0aaf477042/aging-15-204650-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/8fd9cfe78ad4/aging-15-204650-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64f4/10188348/84f270b1497f/aging-15-204650-g006.jpg

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Ubiquitin-proteasome system-mediated ubiquitination modification patterns and characterization of tumor microenvironment infiltration, stemness and cellular senescence in low-grade glioma.

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[1]
USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.

Nat Commun. 2022-3-31

[2]
UBE2B promotes ovarian cancer growth via promoting RAD18 mediated ZMYM2 monoubiquitination and stabilization.

Bioengineered. 2022-4

[3]
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Semin Cancer Biol. 2022-11

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Transl Cancer Res. 2019-10

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Cells. 2021-12-29

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Cells. 2021-6-4

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Aging (Albany NY). 2021-6-8

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Int J Mol Sci. 2021-5-27

[9]
Targeting Ubiquitin-Proteasome System With Copper Complexes for Cancer Therapy.

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[10]
Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9.

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