鞘氨醇激酶2(SphK2) 代谢失衡促进慢性结肠炎微环境形成及炎癌转化研究

项目名称： 鞘氨醇激酶2(SphK2) 代谢失衡促进慢性结肠炎微环境形成及炎癌转化研究

项目编号： No.91629303

项目类型： 重大研究计划

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 曲显俊

作者单位： 首都医科大学

项目金额： 160万元

中文摘要： 结肠组织易缺氧、形成慢性肠炎及炎性腺瘤增生等，原因不明。前期发现，SphK2代谢失衡与结肠癌有关。与SphK1不同，SphK2功能不清。假设SphK2是导致肿瘤微环境主要原因，SphK2表达与代谢异常促进结肠炎癌转化。在建立Sphk2+/+和APCMin/+Sphk2+/+小鼠及分子影像技术确证基础上，分析结肠和淋巴组织肿瘤相关淋巴细胞被招募和驯化状况，分析SphK2上调PD-L1/PD-1及M2、MCSCs浸润，确定Sphk2通过激活免疫逃逸方式促进结肠炎癌转化。以上述小鼠模型及APCMin/+/Atg5和Sphk2+/+/Atg5小鼠等，在基因组测序基础上，研究SphK2具备“分子开关”调控网络机制，确认内质网应激条件下由于SphK2激活所导致的以Atg5为中心形成的凋亡转向自噬调控过程，促进结肠炎癌转化。项目的意义在于明确SphK2是在慢性结肠炎癌转化节点调控关键网络转向的主要分子。

中文关键词： 鞘氨醇激酶2；慢性结肠炎；炎症微环境；炎癌转化；分子开关

英文摘要： Colonic tissues characterize with hypoxia, formation of colonic inflammation and growth of adenomatous polyposis. The reason has yet unknown. We recently found that development of colonic tumorigenesis is related to SphK2 overexpression and loss of balance in metabolism of products. Unlike well-studied SphK1, little has yet understood the functions of SphK2. Based on our previous results, we hypothesize that overexpression of SphK2 causes the formation of tumour microenvironment (TME) and promotion of malignant progression in colon. Based on the establishment of transgenic mice models and determination by in vivo visualization probes, including mice models of Sphk2+/+ and APCMin/+Sphk2+/+, we will further analyze the tumor-associated lymphocyte recruited and educated by cancer cells with high SphK2. Expression of PD-L1/PD-1 and M2 and MCSCs cells invaded colon cancer tissues will be analyzed to understand the mechanism that cancer cells with high Sphk2 escape from immunological surveillance through regulation of the PD-1/PD-L1 axis. Further, we will investigate the net work involving the regulation of tumor microenvironment and development of colitis-associated cancer. The experiment will be performed in the APCMin/+/Atg5 and Sphk2+/+/Atg5 mice model as well as HCT-116Sphk2 cells. We will understand the function of molecular switch for Sphk2 through the activation of autophagy function in Atg5 and inhibiting apoptosis in the condition of endoplasmic reticulum (ER) stress. The significance for this project is that SphK2 might play crucial roles in the conversion from chronic inflammation to tumorigenesis and further progression of colon cancer.

英文关键词： SphK2;chronic colorectal inflammation;tumour microenvironment (TME);conversion from inflammation to tumorigenesis;molecular switch