大肠癌发病率增长最快，与炎症密切相关，但发病机制不完全清楚，也缺乏有效治疗手段。我们前期以AOM/DSS诱导小鼠结肠炎癌转化为模型，在野生型小鼠中收集了炎癌转化动态标本，通过生物信息学手段分析多种组学数据，初步建立了炎癌转化过程的mRNA/蛋白动态变化规律；另外还发现诱导过程中总有极少数小鼠不产生恶性转化，通过测序揭示了发生与不发生炎癌转化的小鼠肠道菌群差异。最重要的是，在8种补体基因敲除小鼠中发现，C5尤其是C5aR基因敲除后几乎完全阻止结肠炎癌转化，并初步揭示了细胞与分子机制。本课题在上述突破性进展基础上，将构建结肠炎癌转化的调控网络，并与C5a/C5aR信号调控密切结合，揭示关键节点分子并诠释其功能，阻断C5a/C5aR信号或抑制补体激活对炎癌转化的影响；同时，还将在属和种的水平研究菌群对炎癌转化的影响及其机制。研究结果还将在临床样本中验证，并最终为结肠癌预防、诊断和治疗提供新思路。

The incidence of colorectal cancer (CRC) increased fastest among all types of cancer in China. It is highly correlated with inflammation; however, the underlying mechanisms are not fully understood, and it requires the effective therapeutics. Using AOM/DSS-induced inflammation-mediated malignant transformation (MT) mouse model, we collected mouse colon samples of different stages of MT, which were further evaluated in omics-level. The results were used to build up 80 kinds of dynamic changes by bioinformatics method. Meanwhile, we induced MT with AOM/DSS in knockout mice of 8 complement genes, and found that the knockout of C5 gene and especially C5aR gene near-completely impeded the process of MT, in which the underlying mechanisms were primarily illustrated. Moreover, we still interestingly observed that there were consistently a tiny minority of treated mice free from MT. These mouse feces were subsequently harvested for bacterial sequencing in comparison to the mouse feces suffering from MT, and the difference between them was revealed. Therefore, in this proposal we will further establish the regulatory network for colitis MT, and elucidate the detailed molecular mechanisms for C5- and C5aR-KO mice free from colitis-induced MT. Then we will discover the key molecules in the network and their action mechanisms in combined with the C5a/C5aR signaling. In addition, the effect of C5a/C5aR signaling blockade and complement inhibition on colitis-induced MT will also be investigated. Finally, we will further investigate the effect and the underlying mechanisms of colorectal bacteria on colitis-induced MT in the levels of genus and species. These findings will be verified in clinical specimen, and we hope that they will benefit prevention, diagnosis and treatment on CRC.