结直肠癌是世界第三大恶性肿瘤。炎性微环境在结直肠癌化启动中的关键作用仍不明确，至今尚没有合适的反映炎性微环境影响结直肠癌化的自发小鼠模型。Act1基因对结直肠癌作用未见报道。利用自建的巨噬细胞Act1表达抑制的小鼠与自发肠道腺瘤Apc(Min/+)模型小鼠杂交，发现巨噬细胞Act1表达抑制后结直肠肿瘤数目和体积明显增加，生存周期明显缩短；并在早期明显促进结直肠癌化发生；我们通过改变炎性微环境成功构建了新型自发结直肠癌小鼠模型。前期工作提示，抑制巨噬细胞Act1表达能影响巨噬细胞极化及T细胞亚群的分化，造成M2型巨噬细胞和CD4+T细胞增多，分泌IL-17和TNF-α水平升高。本项目拟进一步确定改变炎性微环境创建的自发结直肠癌小鼠模型的优势及病理诊断标准；阐明巨噬细胞Act1调控M1/M2极化及促进癌化的免疫分子机制，为以炎性微环境为靶点防治结直肠癌提供新策略。

Colorectal cancer (CRC) is the world's third most common malignant tumour. Inflammatory microenvironment plays an important role in the development of CRC, but its part in the initiation of colorectal cancer still remains to be elucidated. Act1(NF-κB activator 1) is primarily involved in the physiological and pathological processes of inflammation and autoimmune diseases. However, there are limited researches focusing on the role of Act1 in carcinogenesis of CRC. In the present project, anti-Act1 genetically engineered mouse, whose macrophages are deprived of Act1 expression, was crossed with Apc(Min/+) mouse to investigate the impact of macrophage-derived Act1 on the carcinogenesis process of CRC. Our data shows that repression of macrophage-derived Act1 can significantly promote the initiation of cancerization in Apc(Min/+) mouse model, thereby we successfully established a novel model of spontaneous colorectal cancer. The preliminary data indicate that specific repression of Act1 in macrophages can affect macrophage polarization and T cell differentiation, resulting in an elevated ratio of M2 type macrophages and CD4+T cells as well as increased secretion of cytokines IL-17 and TNF-α in the tumour microenvironment, henceforth the promotion of neoplasia in CRC. This project is to to further evaluate the advantages of modulating the inflammatory microenvironment along with the pathological diagnostic criteria in characterizing a novel spontaneous colorectal cancer mouse model, and to elucidate the molecular mechanism for regulation of M1/M2 polarization and T cell differentiation and promotion of carcinogenesis in CRC, with the aim of providing insight into the development of novel anticancer therapies by targeting tumour-associated inflammatory microenvironment.