具核梭杆菌感染来源外泌体激活食道鳞状细胞癌自噬通路影响糖代谢重编程的机制研究

食道鳞状细胞癌术后易复发转移严重影响患者的预后。申请人前期发现肿瘤内具核梭杆菌DNA水平与食道鳞癌化疗疗效相关，通过自噬途径对化疗药物多西紫杉醇、5-氟尿嘧啶和顺铂产生耐药性。通过抑制自噬可以逆转食道鳞癌细胞的化疗耐药。本项目拟在此工作基础上，进一步阐述具核梭杆菌感染促进食道鳞癌细胞外泌体的分泌，此外泌体选择性携带ANXA3蛋白，被未感染癌细胞内化，通过整合素β1激活自噬通路影响食道鳞癌细胞的糖代谢重编程。进一步建立裸鼠食道鳞癌皮下移植瘤模型，获得体外、体内双重证据。最后在临床样本中验证高丰度的具核梭杆菌可以促进携带ANXA3外泌体的释放，探讨具核梭杆菌感染来源外泌体与食道鳞癌发生发展的相关性，揭示具核梭杆菌作为治疗食道鳞癌的靶点的临床转化意义。

The recurrence and metastasis of Oesophageal squamous cell carcinoma (ESCC) seriously affect the prognosis of patients. The applicant found that the DNA level of Fusobacterium nucleatum in the tumor was related to the chemotherapeutic response of ESCC, and induced the chemoresistance to docetaxel, 5-fluorouracil and cisplatin through autophagy pathway. The chemoresistance of ESCC could be reversed by inhibiting autophagy. On the basis of this work, this project intends to further explain that Fusobacterium nucleatum promotes the secretion of exosomes of ESCC. In addition, exosomes selectively carry ANXA3 protein and are internalized by uninfected cancer cells. The reprogramming of glucose metabolism of uninfected ESCC is modulated by autophagy pathway via Integrin β1. The subcutaneous transplanted tumor model of ESCC in nude mice was further established, and the double evidence in vitro and in vivo was obtained. Finally, it is verified in clinical samples that high abundance of Fusobacterium nucleatum can promote the release of ANXA3-carrying exosomes, explore the correlation between the exosomes derived from Fusobacterium nucleatum and the occurrence and development of ESCC, and reveal the clinical transformation significance of Fusobacterium nucleatum as a target for the treatment of ESCC.