秦环龙+刘俊彦+马延磊:具核梭杆菌促肠癌的新机制
  • 结直肠癌(CRC)患者和CRC小鼠模型的肿瘤细胞中,细胞色素P450单加氧酶(主要是 CYP2J2)及其介导的产物12,13-EpOME上调,进而通过激活体外上皮间质转化 (EMT),促进CRC细胞在体内的侵袭和迁移;
  • CRC患者粪便具核梭杆菌(Fn)水平与血清12,13-EpOME水平呈正相关;
  • 肿瘤组织中高水平的CYP2J2,也与III/IV期CRC患者的高Fn水平和较差的总生存期相关;
  • 机制上,Fn可激活TLR4/AKT信号,下调Keap1并增加NRF2以促进CYP2J2转录。
主编推荐语
NL
研究表明细菌能调控结直肠癌(CRC)代谢。同时,具核梭杆菌(Fusobacterium nucleatum, Fn)在结直肠癌的发生发展中起着至关重要的作用。然而,Fn感染是否改变结直肠癌患者的代谢仍不清楚。Cancer Research近期发表了同济大学上海第十人民医院秦环龙、重庆医科大学刘俊彦、复旦大学马延磊与团队的研究成果,使用液相色谱-串联质谱为基础的靶向代谢组学、宏基因组测序、细胞分析和无菌基因敲除小鼠模型进行研究,结果发现Fn感染可激活TLR4/AKT/Keap1/NRF2信号,上调CRC细胞中CYP2J2的表达,进而增加12,13-EpOME的产生,最终导致CRC的发生。本研究不仅拓展了我们对Fn在结直肠癌发生发展中所起作用的认识,而且为Fn感染的结直肠癌患者提供了新的潜在临床生物标志物和治疗靶点。
关键字
延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!
图片
Cancer Research [IF:13.312]

Fusobacterium nucleatum promotes the development of colorectal cancer by activating a cytochrome P450/epoxyoctadecenoic acid axis via TLR4/Keap1/NRF2 signaling

具核梭杆菌通过 TLR4/Keap1/NRF2 信号通路激活细胞色素 P450/环氧十八碳烯酸轴促进结直肠癌的发展

10.1158/0008-5472.CAN-21-0453

2021-06-23, Article

Abstract & Authors:展开

Abstract:收起
Emerging research has revealed regulation of colorectal cancer (CRC) metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of CRC; however, whether Fn infection modifies metabolism in CRC patients 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 CRC patient tumors and mouse models, which increased the invasive and migratory ability of CRC 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 CRC patients. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in stage III/IV CRC patients. 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 CRC 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 CRC patients.

First Authors:
Cheng Kong,Xuebing Yan,Yefei Zhu,Huiyuan Zhu

Correspondence Authors:
Yanlei Ma,Jun-Yan Liu,Huanlong Qin

All Authors:
Cheng Kong,Xuebing Yan,Yefei Zhu,Huiyuan Zhu,Ying Luo,Peipei Liu,Sylvain Ferrandon,Matthew F Kalady,Renyuan Gao,Jide He,Fang Yin,Xiao Qv,Jiayi Zheng,Yaohui Gao,Qing Wei,Yanlei Ma,Jun-Yan Liu,Huanlong Qin

评论