Fusobacterium Nucleatum 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. 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.

Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality

“…Mechanistically, F. nucleatum can active the TLR4/Keap1/NRF2 pathway then up-regulates CYP2J2, a cytochrome P450. Then 12,13-EPOME, a metabolite of CYP2J2, can activate EMT in vitro and promote metastasis of CRC in vivo (Kong et al, 2021).…”

Colorectal cancer: the facts in the case of the microbiota

“…The positive correlation between CRC Fn bacterial load and shortened time to progression may relate to activation of these pathways. TLR4 signaling can intersect with many host cell biological pathways, and a recent study found that TLR4 activation led to AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2 (102). Identification of this pathway helped explain an observation from a paired metagenomics and lipidomics study showing that high levels of fusobacteria in CRC patient tumors and the presence of Fn in DSS-AOM tumors in mice led to increased serum levels of the polyunsaturated fatty acid 12,13-epoxyoctadecenoic acid.…”

“…Identification of this pathway helped explain an observation from a paired metagenomics and lipidomics study showing that high levels of fusobacteria in CRC patient tumors and the presence of Fn in DSS-AOM tumors in mice led to increased serum levels of the polyunsaturated fatty acid 12,13-epoxyoctadecenoic acid. In experiments with 12,13-epoxyoctadecenoic acid, the investigators found that it enhanced cancer cell invasion, migration, and tumor size (102). With all these potential mechanisms at play in preclinical models, it seems important to determine which Fn strains and behaviors are important to target for prevention and treatment of CRC.…”

Nrf2 in the Field of Dentistry with Special Attention to NLRP3

“…In addition, F. nucleatum plays an important role in the development of colorectal cancer, and was shown to promote metastasis by the TLR4/Keap1/Nrf2 axis [ 154 ].…”