Fusobacterium调控NOTCH-ABC信号通路在结肠肿瘤干细胞耐药性中的作用及机制研究

结直肠癌是世界范围内癌症死亡率增加的主要原因，多数晚期患者死于肿瘤耐药，但其机制并不清楚。肿瘤干细胞的发现揭示了其具有更强的抵抗化放疗的能力，明确了化疗失败的一个重要机制是肿瘤干细胞的耐药性，这为研究耐药机制找到了方向。肠道菌群数量庞大，编码基因众多，与人类的健康息息相关，最新的研究表明其可能参与多种消化道肿瘤的发生发展。本课题组前期研究发现肠道菌群中的梭杆菌属在结直肠癌复发患者的标本中富集，从通路富集分析和前期实验，我们发现梭杆菌属可能刺激结肠癌干细胞增殖并涉及NOTCH通路，我们提出假设：梭杆菌属可能通过调节NOTCH通路受体激活结肠肿瘤干细胞耐药性中关键信号通路ATP结合的药物转运蛋白，进而引起结肠肿瘤干细胞耐药。本研究拟通过基因组、生物信息学、生物学、体内模型和临床研究等方面检验和证实该假设。这将为结肠癌干细胞耐药判断和治疗提供新的靶点，并为揭开肿瘤耐药复杂的调控网络提供新的思路。

Colorectal cancer is the main cause of the increase in cancer mortality worldwide, and most advanced patients die from tumor resistance, but the mechanism is not clear. The discovery of cancer stem cells reveals that it has stronger resistance to chemoradiotherapy. An important mechanism for the failure of chemotherapy is the drug resistance of cancer stem cells, which provides a direction for studying the mechanism of drug resistance. The number of intestinal microflora is large, and the coding genes are numerous, which is closely related to human health. The latest research shows that it may participate in the development of many kinds of digestive tract tumors. Our previous study found that Fusobacterium in intestinal flora in recurrent colorectal cancer specimens was enrichment. By pathway enrichment analysis and experiment, we found that Fusobacterium may stimulate the proliferation of colon cancer stem cells and involve 6 key signaling pathway. We hypothesized that Fusobacterium may regulate NOTCH pathway receptor expression in colon cancer stem cell drug resistance in NOTCH-ABC key signaling pathways, thereby causing the colon cancer stem cell chemoresistance. This study is intended to test and verify the hypothesis by genome, bioinformatics, biology, in vivo models, and clinical studies. This will provide new targets for the diagnosis and treatment of colon cancer stem cell resistance, and provide new ideas for uncovering the complex regulatory network of chemoresistance.