在氧化应激过程中,8-氧鸟嘌呤DNA糖基化酶-synaptotagmin 7途径会增加细胞外囊泡的释放并促进肿瘤转移。

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-09-05 DOI:10.1002/jev2.12505
Ying Ma, Jiarong Guo, Haipeng Rao, Jingyu Xin, Xinyi Song, Rui Liu, Shan Shao, Jiajia Hou, Liyu Kong, Zhigang Hu, Lingfeng He, Feiyan Pan, Zhigang Guo
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引用次数: 0

摘要

活性氧(ROS)诱导的 DNA 氧化损伤被认为是基因突变的主要原因,而基因突变与癌变和肿瘤进展高度相关。细胞外囊泡在癌症转移中发挥着重要作用。然而,DNA氧化损伤在细胞外囊泡介导的癌细胞迁移和侵袭中的确切作用仍不清楚。在这里,我们揭示了 ROS 介导的 DNA 氧化损伤信号通过增加 EVs 释放促进肿瘤转移。从机理上讲,8-氧鸟嘌呤 DNA 糖基化酶(OGG1)识别并与其底物 8-氧代-7,8-二氢鸟嘌呤(8-oxoG)结合,将 NF-κB 募集到突触柄蛋白 7(SYT7)启动子上,从而触发 SYT7 的转录。SYT7 表达的上调导致 E-cadherin 负载的 EVs 释放增加,从而消耗细胞内的 E-cadherin,从而诱导上皮-间质转化(EMT)。值得注意的是,OGG1 DNA结合活性抑制剂Th5487能阻断氧化信号的识别和传递,减轻SYT7的表达并抑制EVs的释放,从而阻止肿瘤在体外和体内的进展。总之,我们的研究阐明了 8-oxoG/OGG1/SYT7 轴驱动的 EVs 释放在氧化应激诱导的肿瘤转移中的重要作用。这些发现加深了人们对癌症进展分子基础的理解,并为治疗干预提供了潜在途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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The 8-oxoguanine DNA glycosylase-synaptotagmin 7 pathway increases extracellular vesicle release and promotes tumour metastasis during oxidative stress

Reactive oxygen species (ROS)-induced oxidative DNA damages have been considered the main cause of mutations in genes, which are highly related to carcinogenesis and tumour progression. Extracellular vesicles play an important role in cancer metastasis. However, the precise role of DNA oxidative damage in extracellular vesicles (EVs)-mediated cancer cell migration and invasion remains unclear. Here, we reveal that ROS-mediated DNA oxidative damage signalling promotes tumour metastasis through increasing EVs release. Mechanistically, 8-oxoguanine DNA glycosylase (OGG1) recognises and binds to its substrate 8-oxo-7,8-dihydroguanine (8-oxoG), recruiting NF-κB to the synaptotagmin 7 (SYT7) promoter and thereby triggering SYT7 transcription. The upregulation of SYT7 expression leads to increased release of E-cadherin-loaded EVs, which depletes intracellular E-cadherin, thereby inducing epithelial-mesenchymal transition (EMT). Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8-oxoG/OGG1/SYT7 axis-driven EVs release in oxidative stress-induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention.

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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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