Influence of Citrobacter Freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer.

BACKGROUND:Oxaliplatin, a third-generation platinum-based chemotherapeutic agent, is widely used in the treatment of colorectal cancer (CRC). However, some patients do not respond effectively to oxaliplatin, and intrinsic resistance to the drug poses a significant challenge. Recent studies have revealed an association between the gut microbiome and the progression of CRC. We hypothesized that Citrobacter freundii, a component of the gut microbiome, contributes to oxaliplatin resistance by regulating specific gene expression in CRC cells. METHODS:A bacterial culture filtrate from Citrobacter freundii was employed in the experiments. The CRC cell line RKO, following exposure to this filtrate, was analyzed using high-throughput RNA sequencing. Candidate genes were identified through MTT assays, siRNA knockdown, and overexpression experiments. Apoptosis and reactive oxygen species (ROS) assays were performed to investigate the underlying mechanisms. Finally, a xenograft mouse model was used to evaluate oxaliplatin resistance in vivo. RESULTS:Exposure to bacterial culture filtrate from Citrobacter freundii induced oxaliplatin resistance in RKO cells with downregulation of the NINJ2 gene as a possible molecular mechanism. ReducedNINJ2 gene expression suppressed oxaliplatin-induced apoptosis and ROS generation. A tendency toward reduced oxaliplatin efficacy was observed in vivo when NINJ2 gene expression was suppressed. CONCLUSION:This study demonstrates that Citrobacter freundii promotes oxaliplatin resistance in CRC through downregulation of NINJ2 gene. NINJ2 gene may serve as a predictive biomarker and therapeutic target to overcome oxaliplatin resistance in CRC.