具核梭杆菌诱导肠上皮细胞DNA损伤在大肠肿瘤发生中的作用及机制研究

Many researchers believed that human gut microbiota played an important role in the occurrence and progression of CRC, so it has been one of hot topics to study the role and machanism of intestinal bacteria in the occurrence and progression of CRC. But the mechanism of the intestinal bacteria Fusobacterium nucleatum to promote the occurrence of CRC remains little understood. In our previous study, we found that the proportion of Fusobacterium nucleatum in has been gradually increased in the “normal-adenoma-carcinoma” sequence through our high-throughput sequencing data. Furthermore, we clarified that Fusobacterium nucleatum could promote the occurrence of CRC both in APC(Min/+) mice and wild type C57 mice which induced with DMH, and could induce the DNA damage of intestinal epithelial cells, based on animals experiment combined with cells experiment. But the more elucidated mechanism remained to be further revealed. Based on our preliminary data we will 1. demonstrate Fusobacterium nucleatum can induce the DNA damage to the colon epithelium cell and promote the occurrence of CRC in vivo and in vitro; 2. evaluate the mechanism by which Fusobacterium nucleatum induces DNA damage effect is TGF-β1/Smad3 pathway. In a word, our research may provide new ideas and theoretical basis for the effect and mechanism of gut microbiota in the occurrence and progression of CRC.

大肠肿瘤(CRC)是一种严重危害人类健康的疾病，肠道菌群与CRC发生发展关系的研究已成为当前的热点之一。迄今具核梭杆菌在CRC发生中的作用机制仍知之甚少。我们前期通过高通量测序结合动物研究发现，具核梭杆菌在CRC的“腺瘤-腺癌”发生途径中逐渐富集，且可促进小鼠结肠肿瘤的发生并诱导肠上皮细胞DNA损伤。但其作用机制还有待进一步探讨。为此，我们提出假说，具核梭杆菌可能通过介导TGF-β1/Smad3途径活化诱导肠上皮细胞DNA损伤，进而促进CRC的发生。本研究欲通过APC(Min/+)小鼠体内实验、细胞实验结合临床标本，从分子、细胞、组织以及动物整体水平等多方面阐明①具核梭杆菌可诱导肠上皮细胞DNA损伤并促进CRC的发生；②具核梭杆菌可能通过TGF-β1/Smad3途径参与诱导肠上皮细胞DNA损伤。有助于更好地认识肠道细菌在CRC发生中的作用机制，为CRC的治疗提供新的思路和理论依据。

大肠肿瘤(CRC)是一种严重危害人类健康的疾病，肠道菌群与CRC发生发展关系的研究已成为当前的热点之一。迄今具核梭杆菌在CRC发生中的作用机制仍知之甚少。我们前期通过高通量测序结合动物研究发现，具核梭杆菌在CRC的“腺瘤-腺癌”发生途径中逐渐富集，且可促进小鼠结肠肿瘤的发生并诱导肠上皮细胞DNA损伤。但其作用机制还有待进一步探讨。为此，本研究通过APC(Min/+)小鼠体内实验、细胞实验结合临床标本，从分子、细胞、动物整体水平等多方面阐明①具核梭杆菌可诱导肠上皮细胞DNA损伤并促进CRC的发生；②具核梭杆菌可能通过p-ATM/p-ATR/p-chk2/p-chk1途径参与诱导肠上皮细胞DNA损伤。有助于更好地认识肠道细菌在CRC发生中的作用机制，为CRC的治疗提供新的思路和理论依据。