Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keapl/NRF2 Signaling
Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keapl/NRF2 Signaling
复制标题
具核梭杆菌通过 TLR4/Keap1/NRF2 信号传导激活细胞色素 P450/环氧十八烯酸轴，促进结直肠癌的发展
DOI：
10.1158/0008-5472.can-21-0453
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发表时间：
2021-09-01
期刊：
影响因子：
11.2
通讯作者：
Qin, Huanlong
中科院分区：
文献类型：
--
作者：
Kong, Cheng;Yan, Xuebing;Qin, Huanlong
这项研究揭示了具核梭杆菌调节结直肠癌代谢以驱动转移的机制，表明CYP 2 J2/12，13-EpOME轴在Fn感染患者中的潜在生物标志物和治疗效用。新兴的研究揭示了细菌对结直肠癌代谢的调节。具核梭杆菌（Fn）在结直肠癌的发生中发挥着至关重要的作用，然而，Fn感染是否会改变结直肠癌患者的代谢仍不清楚。在此，基于LC-MS/MS的脂质组学鉴定了结直肠癌肿瘤患者和小鼠模型中细胞色素P450单加氧酶（主要是CYP 2 J2）及其介导产物12，13-EpOME的上调，这通过调节上皮-间充质转化（EMT）增加了结直肠癌细胞在体内和体外的侵袭和迁移能力。宏基因组测序表明，大肠癌患者粪便Fn和血清12，13-EpOME水平升高之间呈正相关。肿瘤组织中高水平的CYP 2 J2也与III/IV期结直肠癌患者的高Fn水平和较差的总生存期相关。此外，发现Fn激活TLR 4/AKT信号传导，下调Keap 1并增加NRF 2以促进CYP 2 J2的转录。总的来说，这些数据确定Fn通过激活TLR 4/Keap 1/NRF 2轴以增加CYP 2 J2和12，13-EpOME来促进结直肠癌中的EMT和转移，这可以作为Fn感染的结直肠癌患者的临床生物标志物和治疗靶点。重要性：这项研究揭示了具核梭杆菌调节结直肠癌代谢以驱动转移的机制，表明CYP 2 J2/12，13-EpOME轴在Fn感染患者中的潜在生物标志物和治疗效用。
This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13-EpOME axis in Fn-infected patients. Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial–mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. Significance: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13–EpOME axis in Fn-infected patients.