炎症小体非依赖的AIM2在结肠癌化学预防中的作用及机制研究

Colorectal cancer is one of the most common malignant tumor in our country. The role of AIM2 inflammasome in inflammation is well characterized, while its role in cancer development is unclear. Hyperactivation Wnt/β-catenin signaling pathway is closely related to colorectal cancer. However，the exact factors which mediate Wnt/β-catenin pathway in colorectal cancer are still unclear. In our preliminary study, we found that the protective effect of AIM2 against colon cancer might be due to its downregulation of the phosphorylation of GSK3β and therefore inhibits the activation of the Wnt/β-catenin pathway. We then screened a series of compounds which were derived from Genistein, and found that one of the most potent compounds –GEN-27 significantly increased the mRNA and protein expressions of AIM2. Furthermore, GEN-27 protected mice against tumorigenesis induced by AOM-DSS, and the potential mechanism could involve the Wnt/β-catenin pathway. In vitro study found that activating AIM2 can inhibit the Wnt/β-catenin pathway, and the effect of GEN-27 on AIM2 and Wnt/β-catenin pathway is independent of AIM2 inflammasome activation, indicating the tumor suppression activity of AIM2 may involve Wnt/β-catenin pathway. The aim of this study is to investigate the role of AIM2 signaling in the development of intestinal tumor induced by AOM/DSS, APC deletion, and AOM/HCD in WT, AIM2-/- and ASC-/- mouse, and illustrate the mechanisms of how AIM2 is involved in the progression of colorectal cancer and how AIM2 mediates Wnt/β-catenin pathway. The result of this study would shed light on the prevention of the colorectal cancer.

AIM2炎症小体在炎症中的作用被广泛接受，但在肿瘤发生发展中的作用尚不清楚。本课题组研究表明：在小鼠结肠癌模型中，模型组AIM2蛋白表达水平下降，p-GSK3β水平显著上调，Wnt/β-catenin信号通路异常活化；金雀异黄素衍生物GEN-27能上调AIM2，抑制β-catenin通路，抑制肠道肿瘤形成；体外实验显示，HT29细胞中GEN-27可上调AIM2，抑制β-catenin入核及其转录活性和靶基因表达，而该作用不依赖于AIM2炎症小体的激活，提示AIM2对于结肠癌的抑制作用可能是通过影响GSK3β磷酸化失活而抑制β-catenin通路的活化实现的。本项目旨在运用细胞模型结合AIM2和ASC敲除小鼠肠癌模型，阐明AIM2不依赖于炎症小体激活的抑癌作用及机制，以及AIM2靶向化学药物对结肠癌的保护作用，为结肠癌发病机制的研究提供新视点，同时对结肠癌化学预防药物的发现具有指导意义。

AIM2炎症小体在炎症中的作用被广泛接受，但在肿瘤发生发展中的作用尚不清楚。我们通过体外研究发现， AIM2蛋白能够通过炎症小体非依赖的Akt通路和炎症小体通路抑制人CRC细胞的EMT过程介导的侵袭转移能力，为基于AIM2的结肠癌预防和治疗方案提供了理论基础。在小鼠AOM/DSS和AOM/HCD结肠癌模型中，模型组AIM2蛋白表达水平下降，p-GSK3β水平显著上调，Wnt/β-catenin信号通路异常活化；金雀异黄素衍生物GEN-27能上调AIM2，抑制β-catenin通路，抑制肠道肿瘤形成。HT29细胞中GEN-27可上调AIM2，抑制β-catenin入核及其转录活性和靶基因表达。AIM2对于结肠癌的预防作用是通过影响GSK3β磷酸化失活而抑制β-catenin通路的活化实现的。我们阐明了AIM2的抑癌作用及机制，以及AIM2靶向化学药物对结肠癌的保护作用，为结肠癌发病机制的研究提供新视点，同时对结肠癌化学预防药物的发现具有指导意义。而另一方面，AIM2作为DNA感受器，能够炎症小体依赖性地促进非小细胞肺癌的发生发展。AIM2的缺失则会造成细胞G2/M期阻滞的发生并抑制Cyclin B1/CDC2复合体的活性。因此，该部分研究为非小细胞肺癌的预防和治疗提供新思路以及理论支持。

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