Ese-3缺失诱发的结肠癌组织微环境改变对树突状细胞功能影响的机制研究

o Blockade of differentiation and maturation in dendric cell (DC) is the most important event for tumor immune escape. So far, the mechanism of tumor immune escape is largely unknown. In previous study, we found that lossing expression of Ese-3 is close related to colorectal cancer development and thus, lead to bad prognosis. Cultural supernatant from HCT116 cell which Ese-3 expression was knockdown and Ese-3-/-colorectal cancer explant model is able to inhibit DC maturation. Higher levels of IL-10 and CXCL1 were detected in cultural supernatant from Ese-3 knockdowned HCT116 cell. And we confirmed that Ese-3 could repress the activity of IL-10 and CXCL1 promoter. Based on these findings, we plan to demonstrate the lossing expression of Ese-3 in colorectal cancer cell causes DC immaturation in colorectal cancer tissue.According to our preliminary study, we plan to analysis discover and identify the target factor of Ese-3 which is related to DC maturation in colorectal cancer mass spectrometry. Furthermore, we will figure out the mechanism of regulating Ese-3 target factor expression by Ese-3 and discuss the reason of silence of Ese-3 expression. our study will disclose the role of Ese-3 in colorectal cancer immune escape.

树突状细胞(DC)分化成熟障碍是导致肿瘤免疫逃逸的重要因素，而荷瘤机体中DC细胞分化成熟障碍的机制并未完全阐明。我们前期发现Ese-3缺失与结肠癌患者预后不良紧密相关；Ese-3沉默的HCT116细胞和Ese-3缺失的结肠癌组织块培养上清可以阻断外周血CD14+单个核细胞被诱导分化成为mDC。ELISA检测发现Ese-3缺失可导致结肠癌细胞培养上清中IL-10和CXCL1水平显著增高并初步证实Ese-3能够有效抑制IL-10、CXCL1启动子活性。我们推测：结肠癌细胞中Ese-3可调控DC分化成熟相关分子；Ese-3缺失诱发或促进结肠癌免疫逃逸。本课题拟证实Ese-3缺失的结肠癌细胞对DC细胞分化成熟和功能的抑制作用；结合前期发现，通过质谱分析等鉴定Ese-3调控的靶分子并初步探讨Ese-3在结肠癌中表达缺失的机理，为阐明结肠癌细胞中Ese-3通过改变微环境诱导免疫逃逸的分子机理奠定基础。

树突状细胞(DC)分化成熟障碍是导致肿瘤免疫逃逸的重要因素，而荷瘤机体中DC 细胞分化成熟障碍的机制并未完全阐明。我们发现 Ese-3 在结肠癌组织中的表达显著低于癌旁组织，Ese-3的缺失与结肠癌患者预后不良紧密相关，在HCT15和SW480结肠癌细胞中过表达Ese-3显著促进结肠癌细胞的增殖，同时研究发现Ese-3主要通过调节MAGI-2进而调节下游PTEN的表达和AKT的磷酸化而调节结肠癌细胞的增殖；Ese-3 沉默的 FHC细胞的培养上清可以阻断外周血CD14+单个核细胞被诱导分化成为 mDC，Ese-3 过表达的SW480细胞的培养上清可以促使外周血CD14+单个核细胞被诱导分化成为 mDC，同时研究证实Ese-3过表达的SW480可以促进肿瘤细胞膜上CD80的上调。ELISA 检测发现 Ese-3 缺失可导致结肠癌细胞培养上清中 IL-10 和 CXCL1 水平显著增高并初步证实 Ese-3 能够有效抑制 IL-10、 CXCL1 启动子活性。我们研究证实：Ese-3 缺失或过表达的结肠癌细胞可以调控 DC 细胞分化成熟； Ese-3 缺失诱发或促进结肠癌免疫逃逸，并通过ChIP实验等鉴定 Ese-3 调控的靶分子并初步探讨 Ese-3 在结肠癌中表达缺失的机理，为阐明结肠癌细胞中 Ese-3 通过改变微环境诱导免疫逃逸的分子机理奠定基础。