Wang Pengcheng, Huang Qiaozhen, Zhu Yuejia, Chen Liquan, Ye Kai
Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, No. 34, Zhongshan North Road, Fuzhou, 362000, China.
Adv Biol (Weinh). 2024 Dec;8(12):e2400293. doi: 10.1002/adbi.202400293. Epub 2024 Sep 27.
Fusobacterium nucleatum (Fn) is significantly associated with poor prognosis in colorectal carcinoma (CRC), however, mechanisms of Fn in DNA mismatch repair (MMR) and microsatellite instability (MSI) in CRC have not been fully elucidated. Clinical samples are collected to analyze the relationship between Fn abundance and microsatellite stability. Tumor cells are treated with Fn to detect the expression of proteins related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88), mutS homolog 6 (MSH6), and nuclear factor-κB (NF-κB) signaling pathways, respectively. Combined with the prediction results from TargetScan, the regulatory role of microRNA upstream of MSH6 is demonstrated. The effect of this regulatory axis on CRC development is demonstrated using a nude mouse tumor model. Compared with microsatellite stability (MSS)-type CRC patients, MSI-type showed higher Fn abundance. Fn treatment of CRC cells activated TLR4/Myd88/NF-κB signaling pathway, transcriptionally activating miRNA-155-5p expression, thereby negatively regulating MSH6. Fn treatment accelerated the malignant progression of CRC in mice, and this process is inhibited by miRNA-155-5p antagomir. Fn in CRC upregulated miRNA-155-5p by activating TLR4/NF-κB signaling to inhibit MSH6, and this regulatory pathway may affect MSS of cancer cells.
具核梭杆菌（Fn）与结直肠癌（CRC）的不良预后显著相关，然而，Fn在CRC的DNA错配修复（MMR）和微卫星不稳定性（MSI）中的作用机制尚未完全阐明。收集临床样本以分析Fn丰度与微卫星稳定性之间的关系。用Fn处理肿瘤细胞，分别检测与Toll样受体4（TLR4）、髓样分化因子88（Myd88）、错配修复蛋白6（MSH6）和核因子-κB（NF-κB）信号通路相关的蛋白表达。结合TargetScan的预测结果，证实了MSH6上游微小RNA的调控作用。使用裸鼠肿瘤模型证实了该调控轴对CRC发展的影响。与微卫星稳定（MSS）型CRC患者相比，MSI型患者的Fn丰度更高。Fn处理CRC细胞可激活TLR4/Myd88/NF-κB信号通路，转录激活miRNA-155-5p的表达，从而负向调节MSH6。Fn处理加速了小鼠CRC的恶性进展，而这一过程可被miRNA-155-5p拮抗剂抑制。CRC中的Fn通过激活TLR4/NF-κB信号上调miRNA-155-5p以抑制MSH6，并且这种调控途径可能影响癌细胞的MSS。
