Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer
ABSTRACT 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...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.70940 |
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| author | Reio Ueta Hiroo Imai Ken Saijo Yoshifumi Kawamura Shuto Kodera Chikashi Ishioka |
| author_facet | Reio Ueta Hiroo Imai Ken Saijo Yoshifumi Kawamura Shuto Kodera Chikashi Ishioka |
| author_sort | Reio Ueta |
| collection | DOAJ |
| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-c74b47a9459841e58d2f1f9780c81fc9 |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-c74b47a9459841e58d2f1f9780c81fc92025-08-20T03:58:18ZengWileyCancer Medicine2045-76342025-07-011413n/an/a10.1002/cam4.70940Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal CancerReio Ueta0Hiroo Imai1Ken Saijo2Yoshifumi Kawamura3Shuto Kodera4Chikashi Ishioka5Department of Clinical Oncology Tohoku University Graduate School of Medicine Sendai JapanDepartment of Clinical Oncology Tohoku University Graduate School of Medicine Sendai JapanDepartment of Clinical Oncology Tohoku University Graduate School of Medicine Sendai JapanDepartment of Clinical Oncology Tohoku University Graduate School of Medicine Sendai JapanDepartment of Clinical Oncology Tohoku University Graduate School of Medicine Sendai JapanDepartment of Clinical Oncology Tohoku University Graduate School of Medicine Sendai JapanABSTRACT 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.https://doi.org/10.1002/cam4.70940bacterial culture filtrateCitrobacter freundiicolon cancergut microbiomeoxaliplatin |
| spellingShingle | Reio Ueta Hiroo Imai Ken Saijo Yoshifumi Kawamura Shuto Kodera Chikashi Ishioka Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer Cancer Medicine bacterial culture filtrate Citrobacter freundii colon cancer gut microbiome oxaliplatin |
| title | Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer |
| title_full | Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer |
| title_fullStr | Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer |
| title_full_unstemmed | Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer |
| title_short | Influence of Citrobacter freundii on NINJ2 Expression and Oxaliplatin Resistance in Colorectal Cancer |
| title_sort | influence of citrobacter freundii on ninj2 expression and oxaliplatin resistance in colorectal cancer |
| topic | bacterial culture filtrate Citrobacter freundii colon cancer gut microbiome oxaliplatin |
| url | https://doi.org/10.1002/cam4.70940 |
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