Fusobacterium nucleatum enhances oxaliplatin resistance in colon cancer by increasing PVT1 expression.

[BACKGROUND] Approximately 50% of colorectal cancer (CRC) patients exhibit high levels of Fusobacterium nucleatum (Fn), which is associated with chemotherapy resistance. As Fn itself cannot be directly targeted for therapy in vivo, elucidating the mechanism underlying Fn-induced chemotherapy resistance is crucial, though it remains unclear.

[METHODS] qPCR was used to analyze the correlation between Fn abundance and clinical parameters in 80 human colon cancer samples. The effect of Fn on the sensitivity of colon cancer cells to oxaliplatin was evaluated by clone formation, EdU proliferation and apoptosis assays. RNA sequencing was performed on Fn-infected colon cancer cells to identify differentially expressed genes. Mechanistic studies explored the interaction between PVT1 and ATAD3A, and the role of TLR4/NF-κB pathway in regulating PVT1 expression.

[RESULTS] qPCR experiments showed that Fn abundance was associated with later clinical stage and shorter RFS. Clone formation, EdU proliferation assay and apoptosis assay showed that Fn could change the sensitivity of colon cancer cells to oxaliplatin. Further RNA sequencing showed that Fn infection could upregulate the expression of long noncoding RNA plasmacytoma variant translocation 1 (PVT1) in colon cancer cells. The abundance of Fn in colon cancer tissues was positively correlated with the level of PVT1, and the mechanism was that PVT1 binds to AAA domain protein 3 (ATAD3A) and prevents its ubiquitination. Fn upregulates ATAD3A expression through PVT1 and inhibits ER stress-mediated cell death. In addition, in colon cancer cells co-cultured with Fn, PVT1 expression is regulated by the TLR4/NF-κB pathway.

[CONCLUSIONS] This study delineates a pathway where Fn infection promotes oxaliplatin resistancein colon cancer cells by upregulating PVT1 via the TLR4/NF-κB pathway. PVT1 subsequently stabilizes ATAD3A, suppressing cell death. PVT1 is a potential target to overcome the high abundance of Fusobacterium nucleatum leading to oxaliplatin resistance in colon cancer.