USP22通过去泛素化SND1介导肿瘤相关巨噬细胞极化并促进胰腺癌生长和转移的机制研究

项目名称： USP22通过去泛素化SND1介导肿瘤相关巨噬细胞极化并促进胰腺癌生长和转移的机制研究

项目编号： No.81502024

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 宁振

作者单位： 大连医科大学

项目金额： 18万元

中文摘要： 肿瘤相关巨噬细胞（TAMs）是连接肿瘤进展和肿瘤微环境的重要炎症细胞，可分泌多种细胞因子促进肿瘤生长及转移，这与其多呈巨噬细胞M2极化有关，但确切机制尚不清楚。前期已证实去泛素化酶USP22与胰腺癌生长、侵袭、转移密切相关（Int J Oncol.2014;45(4):1594-1608）。预实验发现巨噬细胞中USP22表达上调可导致M2极化，并促进胰腺癌细胞增殖及迁移。本研究拟利用微流控芯片、免疫共沉淀、裸鼠胰腺癌原位移植瘤模型等技术进行如下研究：1、从组织-体外-体内阐明TAMs中USP22对胰腺癌生长和转移的作用；2、明确USP22在巨噬细胞M2极化中的作用，及其对JAK/STAT6通路和其介导的细胞因子表达谱的影响；3、鉴定一种新的USP22去泛素化底物SND1，探讨其参与USP22 对 JAK/STAT6通路调控的分子机制。本课题有望为胰腺癌免疫治疗提供新策略和新靶点。

中文关键词： 胰腺癌；肿瘤相关巨噬细胞；去泛素化酶USP22；信号传导；肿瘤转移

英文摘要： Tumor-associated macrophages（TAMs）represent the major inflammatory cell population in tumors, which alter the tumor microenvironment to accelerate tumor progression. TAMs promote tumor growth and metastasis through the release of cytokines, which is related to its M2-like phenotype. Our previous data show that USP22 play an important role in the growth, invasion and metastasis of pancreatic cancer, and related to the poor prognosis (Int J Oncol.2014;45(4):1594-1608). Recently, we found that the overexpression of USP22 in macrophages can lead to M2 polarization, which promoting tumor growth and metastasis in pancreatic cancer. In this study, lentiviral transfection, microfluidic chip, immunoprecipitation, pancreatic cancer orthotopic xenograft model in nude mice will be used to do the following research. 1. We will investigate the relationship between USP22 expression in TAM and pancreatic cancer progression from tissue- in vitro- in vivo. 2. We will investigate the role of USP22 in inducing M2 polarization and regulating the JAK/STAT6 pathway and cytokines . 3. We will identify a new substrate protein of USP22—SND1, and explore whether it is involved in the regulation of USP22 to JAK/STAT6 pathway. This research will provide a new idea and target for the immunotherapy of pancreatic cancer , which is based on TAMs in tumor microenvironment.

英文关键词： pancreatic cancer; tumor-associated macrophages ;deubiquitinating enzyme USP22 ;signal transduction;tumor metastasis