巨噬细胞在慢性炎症基础上发生肿瘤的病理过程中扮演关键角色。蛋白质可逆的SUMO化修饰是应激应答反应的重要调控方式，但巨噬细胞炎症信号分子的SUMO化修饰是否调控炎症-癌症微环境则未见报道。我们用巨噬细胞特异性敲除的小鼠模型证明：SUMO蛋白酶SENP3在急性脓毒血症中能激活巨噬细胞炎症反应信号通路。我们最近在幽门螺杆菌+化学致癌剂诱发的胃癌模型中又发现，敲除巨噬细胞SENP3的小鼠炎症减轻、癌变延缓，并伴随胃黏膜T淋巴细胞数目减少和脾脏肿大的逆转。因此，我们拟提出巨噬细胞SENP3调控免疫细胞互作造成的炎症微环境可能参与介导胃炎-胃癌发展过程的假说，将在本项目中利用前期建立的条件性敲除SENP3的小鼠胃炎-胃癌模型，聚焦研究SENP3如何调控巨噬细胞的分化和活化并由此调控T细胞增殖分化进而影响上皮细胞癌变的进程，以阐释SUMO化修饰调控巨噬细胞在慢性炎症基础上的肿瘤发生中的作用机制。

Macrophages play a key role in the pathological process of tumorigenesis on the basis of chronic inflammation. Reversible protein SUMOylation is an important regulator in cell stress response. But, it is not clear whether SUMOylation of inflammatory signaling molecules in macrophages regulates the inflammatory microenvironment of chronic inflammation-based cancers. Using macrophage conditional knockout mouse we previously demonstrated that SUMO protease SENP3 can activate macrophage inflammatory signaling pathway in acute sepsis. Recently, we found in mouse model of gastric cancer induced by Helicobacter pylori and chemical carcinogen that macrophage SENP3 knockout mice, compared to the wild type counterpart, have reduced gastritis and delayed gastric cancer development, accompanied by a decrease of T lymphocytes number in the gastric mucosa and a reversal of spleen enlargement. Therefore, we propose the hypothesis that inflammatory microenvironment created by immune cell interaction which is modulated by macrophage SENP3 may mediate the development of gastritis to gastric cancer. The present project will use the pre-established gastritis-gastric cancer model with SENP3 conditional knockout mouse to figure out how SENP3 regulates macrophage differentiation and activation, and then affects T cell proliferation and differentiation during epithelial carcinogenesis progress. The purposes of this study are to elucidate the roles of SUMOylation in regulating macrophages in chronic inflammation-based carcinogenesis.