炎癌转化是结肠癌发病过程中的关键节点，但原因与机制不清。在建立结肠炎癌转化模型基础上，假设SphK2是导致肿瘤微环境的原因、其异常表达促进了炎癌转化进程。拟以高表达Sphk2+/+和杂合APCMin/+Sphk2+/+小鼠结合细胞方法，分析结肠和淋巴组织等肿瘤相关淋巴细胞被招募和驯化状况，分析SphK2上调癌细胞表面PD-L1/PD-1表达及M2、MCSCs等免疫细胞浸润程度，确认Sphk2通过肿瘤免疫逃逸机制促进了炎癌转化。再以APCMin/+/Atg5和Sphk2+/+/Atg5小鼠及裸鼠接种HCT-116Sphk2方法，通过研究SphK2的“分子开关”机制，确认在内质网应激条件下激活Atg5调控的凋亡转向自噬活动促进了结肠炎癌转化进程。靶向Sphk2的化合物可能抑制上述炎癌转化过程。本项目的意义在于明确了SphK2是导致结肠炎癌转化的关键因子，将为临床制定更加有效的防治方案奠定基础。

The malignant progression from inflammation to tumorigenesis is the critical point in the development of colon cancer. However, the cause and mechanism for colon cancer have still been unknown. Based on the establishment of mice models with high expression of SphK2, we hypothesize that SphK2 cause the formation of tumour microenvironment (TME) and the promotion of malignant progression in colon. The project will be mainly designed in mice models of Sphk2+/+ and APCMin/+Sphk2+/+ as well as cell culture. The experiments will be performed to analyze the number of tumor-associated lymphocyte recruited and educated by cancer cells with high expression of SphK2 in colon cancer tissues and lymphonodus. We will analyze the expression of PD-L1/PD-1 on cancer cells and M2 and MCSCs cells invade in colon cancer tissues. Based on these data, we will conclude that cancer cells with high level of Sphk2 may escape from immunological surveillance through up regulation of the PD-1/PD-L1 axis. Using APCMin/+/Atg5 and Sphk2+/+/Atg5 mice model as well as HCT-116Sphk2 cells, we will investigate the role of molecular switch for Sphk2 through activating the function of autophagy in Atg5 and inhibiting the function of apoptosis in the condition of endoplasmic reticulum (ER) stress. The compound targeting SphK2 might inhibit the malignant progression of colon cancer. The significance for this project is that SphK2 might play crucial roles in the progression of colon cancer. These data will be provided to clinical study for improving the chemoprevention results for colon cancers.