调控肿瘤逃逸NK细胞杀伤的miRNA的发现及机制研究

项目名称： 调控肿瘤逃逸NK细胞杀伤的miRNA的发现及机制研究

项目编号： No.31301066

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 陈勤

作者单位： 上海交通大学

项目金额： 28万元

中文摘要： 关于肿瘤细胞如何逃逸NK细胞杀伤的具体分子机制目前尚未完全清楚。哪些miRNA调控肿瘤细胞表面的配体表达从而介导肿瘤细胞逃逸NK杀伤，国内外研究刚刚起步。本项目拟通过对NK细胞杀伤具有不同敏感性的配对前列腺癌细胞系的miRNA深度测序和基因表达谱高通量测序，找到调控肿瘤细胞逃逸NK杀伤的关键miRNA和蛋白。通过测序和初步的生物功能学验证，我们发现miR-296-3p在肿瘤细胞中的过表达能够抑制NK细胞对其杀伤,可能通过我们新鉴定的靶蛋白ICAM-1实现。在此基础上，我们将从分子、细胞、动物和临床标本这四个层面，系统地检测miR-296-3p与肿瘤细胞逃逸NK杀伤、肿瘤发生和肿瘤转移之间的关系，并考察ICAM-1是否为miR-296-3p发挥上述功能的关键效应分子,从而找到调控肿瘤细胞逃避NK细胞杀伤的新分子机制。最后，我们也将初步探索miR-296-3p成为治疗靶点的可能性。

中文关键词： microRNA；自然杀伤细胞；细胞间粘附蛋白-1；抗肿瘤免疫治疗；

英文摘要： The mechanisms that have been developed by tumor cells to evade NK cell-mediated lysis are not well understood.We are still at the very beginning of the study on what miRNAs regulate the expression of ligands on the surface of tumor cells to modulate tumor susceptibility to NK cells. To address this question, we proposed to perform microRNA deep sequencing and high-throughput whole-genome sequencing on a pair of prostate cancer cell lines that have different susceptibilities to NK cells. According to the sequecing results followed by the verification with biological function assays, we have found that overexpression of miR-296-3p in tumor cells significantly suppressed NK cell cytotoxicity and intercellular adhesion molecule-1 (ICAM-1) which has been identified by us as a new target for miR-296-3p may be involved in this process. Based on these findings, we will examine the effects of miR-296-3p on immune evasion, tumorigenesis and tumor metastasis at molecular, cellular, animal and clinical levels and elucidate the mechanisms involved. miR-296-3p will also be evaluated as a target for anti-tumor therapeutics. A successful outcome will advance our understanding of the mechanisms for immune evasion and provide new target and insight into anti-tumor immune therapy based on NK cells.

英文关键词： microRNA；natural killer cells；ICAM-1；anti-tumor immune therapy；