<i>Fusobacterium Nucleatum</i> Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling

Abstract

Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. <i>Fusobacterium nucleatum</i> (<i>Fn</i>) plays a crucial role in the development of colorectal cancer, however, whether <i>Fn</i> 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 <i>in vivo</i> and <i>in vitro</i> by regulating the epithelial-mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal <i>Fn</i> and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high <i>Fn</i> levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, <i>Fn</i> was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that <i>Fn</i> 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 <i>Fn</i>-infected patients with colorectal cancer. SIGNIFICANCE: This study uncovers a mechanism by which <i>Fusobacterium nucleatum</i> regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13-EpOME axis in <i>Fn</i>-infected patients.