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通过靶向CYP11A1重新分布，由CagA介导的线粒体胆固醇积累促进胃癌。

promotes gastric cancer through CagA-mediated mitochondrial cholesterol accumulation by targeting CYP11A1 redistribution.

作者信息

Zhang Zhijun, Huang Hongxin, Chen Zetian, Yan Mengpei, Lu Chen, Xu Zekuan, Li Zheng

机构信息

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P. R. China.

Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P. R. China.

出版信息

Int J Biol Sci. 2024 Jul 15;20(10):4007-4028. doi: 10.7150/ijbs.96425. eCollection 2024.

DOI:10.7150/ijbs.96425
PMID:39113698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11302876/
Abstract

Cholesterol and () are both risk factors for gastric cancer (GC). However, the relationship between cholesterol and and their function in the progression of GC are controversial. In this study, we addressed that could induce mitochondrial cholesterol accumulation and promote GC proliferation and protect GC cells against apoptosis via cholesterol. Metabolomic and transcriptomic sequencing were used to identify CYP11A1 responsible for -induced cholesterol accumulation. and function experiments revealed that cholesterol could promote the proliferation of GC and inhibit apoptosis. Mechanically, the interaction of Cytotoxin-associated gene A (CagA) and CYP11A1 redistributed mitochondrial CYP11A1 outside the mitochondria and subsequently caused mitochondrial cholesterol accumulation. The CYP11A1-knockdown upregulated cholesterol accumulation and reproduced the effect of cholesterol on GC in a cholesterol-dependent manner. Moreover, CYP11A1-knockdown or infection inhibited mitophagy and maintained the mitochondria homeostasis. could contribute to the progression of GC through the CagA/CYP11A1-mitoCHO axis. This study demonstrates that can contribute to the progression of GC via cholesterol, and eradicating is still prognostically beneficial to GC patients.

摘要

胆固醇和（）都是胃癌（GC）的危险因素。然而，胆固醇与（）之间的关系及其在GC进展中的作用存在争议。在本研究中，我们探讨了（）可诱导线粒体胆固醇积累，促进GC增殖，并通过胆固醇保护GC细胞免受凋亡。采用代谢组学和转录组学测序来鉴定负责（）诱导胆固醇积累的CYP11A1。（）和功能实验表明，胆固醇可促进GC增殖并抑制凋亡。机制上，细胞毒素相关基因A（CagA）与CYP11A1的相互作用使线粒体CYP11A1重新分布到线粒体外，随后导致线粒体胆固醇积累。CYP11A1基因敲低上调胆固醇积累，并以胆固醇依赖的方式重现胆固醇对GC的影响。此外，CYP11A1基因敲低或（）感染抑制线粒体自噬并维持线粒体稳态。（）可通过CagA/CYP11A1-线粒体胆固醇轴促进GC进展。本研究表明，（）可通过胆固醇促进GC进展，根除（）对GC患者仍具有预后益处。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2820/11302876/61fd1f67cede/ijbsv20p4007g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2820/11302876/827c627c9b9a/ijbsv20p4007g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2820/11302876/827c627c9b9a/ijbsv20p4007g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2820/11302876/8d4343ee0814/ijbsv20p4007g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2820/11302876/03debfbcd047/ijbsv20p4007g003.jpg
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