具核梭杆菌诱导结直肠癌产生化疗耐药的机制研究

Colorectal cancer is one of the most common malignant tumors worldwide. Clinically, the current treatment for colorectal cancer is a comprehensive treatment based on surgical resection combined with chemotherapy. However, the patients eventually experience tumor recurrence due to drug resistance, and the 5 year survival rate is lower than 10% in advanced CRC patients. Therefore, it is of great significance to further explore the mechanisms of colorectal cancer chemoresistance and to search for new drug targets for improving the prognosis and quality of life of colorectal cancer patients. Our previous studies have confirmed that Fusobacterium nucleatum can promote tumor resistance to chemotherapy by inducing autophagy pathway in colorectal cancer cells, which could affect the prognosis of colorectal cancer patients. This study will focus on the specific pathogenic components of Fusobacterium nucleatum and the effects of Fusobacterium nucleatum on other chemotherapy drugs for colorectal cancer. We want to further explore the detailed mechanisms of Fusobacterium nucleatum promoting chemoresistance in colorectal cancer, and hope to provide some theoretical guidance about clinical treatment of colorectal cancer.

结直肠癌是最常见的恶性肿瘤之一。在临床上，目前针对结直肠癌的治疗是以手术切除联合化学药物治疗为主的综合性治疗。然而，目前晚期结直肠癌患者的五年生存率仍不足10%，导致肿瘤患者死亡的一个重要原因是其在接受标准化疗后产生的耐药性。因此，进一步探索结直肠癌的耐药机理，寻找新型的药物作用靶点，对于改善结直肠癌患者的预后和生存质量具有重要的临床意义。我们前期研究证实具核梭杆菌可通过诱导结直肠癌自噬增加而促进肿瘤对5-氟尿嘧啶及奥沙利铂产生耐药，从而影响结直肠癌患者的预后。本研究将深入探讨具核梭杆菌引起结直肠癌化疗耐药的具体成分以及更多药物种类，进一步探究具核梭杆菌促进结直肠癌产生化疗抵抗的机制，为结直肠癌化疗耐药这一临床问题提供一定的理论指导。

目的.肠道菌群紊乱会导致肠道慢性炎症甚至结直肠癌。有研究表明糖酵解与结直肠癌患者的预后不良有关。然而，结直肠癌患者的肠道菌群和糖代谢之间的潜在关系尚不清楚。.设计.采用18F-脱氧葡萄糖(18F-FDG)正电子发射断层扫描(PET)/CT图像扫描数据和菌群聚合酶链式反应(PCR)分析方法，分析33例结直肠癌患者代谢改变与肠道菌群紊乱的相关性。本研究建立了多种结直肠癌模型，并通过代谢分析和海马实验评估长链非编码RNA (LncRNA)烯醇化酶1-内含子转录本1 (ENO1-IT1)在具核梭杆菌核诱导的糖代谢和结直肠癌中的作用。通过RNA免疫沉淀和染色质免疫沉淀测序鉴定了lncRNA ENO1-IT1的潜在靶点。.结果.在结直肠癌患者中，我们发现具核梭杆菌的丰度与高糖代谢相关。此外，具核梭杆菌可通过增加结直肠癌细胞的葡萄糖代谢（如上调糖酵解途径中的关键组分ENO1等），从而促进肿瘤的发生。在机制上，具核梭杆菌通过上调转录因子SP1与lncRNA ENO1-IT1启动子区域的结合效率来激活lncRNA ENO1-IT1的转录。升高的ENO1-IT作为组蛋白乙酰转移酶KAT7的引导模块，调控其靶基因(包括ENO1)上的组蛋白修饰模式，从而改变结直肠癌细胞的生物学功能.结论.具核梭杆菌和葡萄糖代谢与结直肠癌的发病机制、生物学行为和临床预后密切相关。靶向ENO1通路可能对治疗高丰度具核梭杆菌的结直肠癌患者有意义。