NDUFS1缺失通过激活线粒体ROS-HIF1α-FBLN5信号通路促进胃癌进展。

Loss of NDUFS1 promotes gastric cancer progression by activating the mitochondrial ROS-HIF1α-FBLN5 signaling pathway.

作者信息

Chen Tao, Li Dongbao, Wang Yunliang, Shen Xiaochun, Dong Anqi, Dong Chao, Duan Kaipeng, Ren Jiayu, Li Weikang, Shu Gege, Yang Jiaoyang, Xie Yufeng, Qian Fuliang, Zhou Jin

机构信息

Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China.

Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, 215006, Suzhou, China.

出版信息

Br J Cancer. 2023 Oct;129(8):1261-1273. doi: 10.1038/s41416-023-02409-5. Epub 2023 Aug 29.

DOI:10.1038/s41416-023-02409-5

PMID:37644092

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10575981/

Abstract

BACKGROUND

Recent studies suggested that NDUFS1 has an important role in human cancers; however, the effects of NDUFS1 on gastric cancer (GC) are still not fully understood.

METHODS

We confirmed that NDUFS1 is downregulated in GC cells through western blot immunohistochemistry and bioinformation analysis. The effect of NDUFS1 on GC was studied by CCK-8, colony formation, transwell assay in vitro and Mouse xenograft assay in vivo. Expression and subcellular localization of NDUFS1 and the content of mitochondrial reactive oxygen species (mROS) was observed by confocal reflectance microscopy.

RESULTS

Reduced expression of NDUFS1 was found in GC tissues and cell lines. Also, NDUFS1 overexpression inhibited GC cell proliferation, migration, and invasion in vitro as well as growth and metastasis in vivo. Mechanistically, NDUFS1 reduction led to the activation of the mROS-hypoxia-inducible factor 1α (HIF1α) signaling pathway. We further clarified that NDUFS1 reduction upregulated the expression of fibulin 5 (FBLN5), a transcriptional target of HIF1α, through activation of mROS-HIF1α signaling in GC cells.

CONCLUSIONS

The results of this study indicate that NDUFS1 downregulation promotes GC progression by activating an mROS-HIF1α-FBLN5 signaling pathway.

摘要

背景

最近的研究表明，NDUFS1在人类癌症中起重要作用；然而，NDUFS1对胃癌（GC）的影响仍未完全了解。

方法

我们通过蛋白质免疫印迹、免疫组织化学和生物信息分析证实了NDUFS1在GC细胞中表达下调。通过CCK-8、集落形成、体外Transwell实验和体内小鼠异种移植实验研究了NDUFS1对GC的影响。通过共聚焦反射显微镜观察NDUFS1的表达和亚细胞定位以及线粒体活性氧（mROS）的含量。

结果

在GC组织和细胞系中发现NDUFS1表达降低。此外，NDUFS1过表达在体外抑制GC细胞增殖、迁移和侵袭，在体内抑制其生长和转移。机制上，NDUFS1表达降低导致mROS-缺氧诱导因子1α（HIF1α）信号通路激活。我们进一步阐明，NDUFS1表达降低通过激活GC细胞中的mROS-HIF1α信号通路，上调了HIF1α的转录靶点纤连蛋白5（FBLN5）的表达。