APC突变可能致Wnt-β-catenin异常传导，并与参入的炎症信号相互影响形成新的网络通路。我们拟以APCMin+背景建立的APCMin+/Fas deficiency，APCMin+/COX transgenes和APCMin+/Vegfr2-KI(knock in)肠癌小鼠模型，研究APC背景下如何影响Wnt-异常传导，产生新炎症信号传递网络过程。假设这些新模型的肠微腺瘤形成与癌变过程中存在以下信号网络：①炎症信号循NF-κB-COX-2/PGE2-MMP-7-Fas/CD95异常传导介导肠腺瘤增殖、凋亡抵抗；②炎症因子对PPAR家族网络信号激活可能介导肠微腺瘤恶变和增殖作用；③炎症对Ras-Raf(MAP KKK)-MAPK/ERK1/2-MMPs激活可能传递浸润转移信号；④COX-2/PGE2-KDR-Shb-PI3K-AKT的异常传导可能促进微血管形成和肠上皮-间质化EMT。

In this study, we aim to investigate the molecular mechanisms of intestinal adenoma and colorectal cancer (CRC). Many studies showed that the mutation of APC gene, adenomatous polyposis coli (APC), would affect the signal pathway of Wnt-β-catenin. Using the new models of intestinal cancer with double specific targets, including the mice models of APCMin+/Fas deficiency, APCMin+/COX transgenes and APCMin+/Vegfr2-KI(knock in), we investigate the mechanisms of the interaction of APC mutation and dysregulation of the Wnt signaling pathway in the intestinal adenomas. We hypothesize that APC mutation could induce the dysregulation of the Wnt-β-catenin and then resulted in a series of new related signaling pathways in the development of colorectal cancer from intestinal adenoma in the background of APC mutation. The growth and invasion of intestinal adenomas are increased exposure to inflammatory stress. Based on these expectations, we hypothesize the following new signaling pathways. (1) The formation and development of intestinal adenoma are associated with the activation of NF-κB-COX-2/PGE2-MMP-7-Fas/CD95 in intestinal adenomas. (2) The development of CRC from intestinal adenoma might due to the involvement of activation of protein from PPAR family. (3) The invasion and metastasis of colorectal cancer cells might be due to increase of activity of Ras-Raf(MAP KKK)-MAPK/ERK1/2-MMPs. (4) The stimulation of signaling pathway COX-2/PGE2-KDR-Shb-PI3K-AKT or KDR-PLC-γ-PKC-Raf-MEK-MAPK might increase the formation of EMT and angiogenesis in the tissues of colorectal cancers. These studies will find the new way of investigation in the regimen in chemoprevention against intestinal tumorigenesis.