DLC3受MACC1抑制引起胃癌细胞EMT逃避代谢应激的机制

项目名称： DLC3受MACC1抑制引起胃癌细胞EMT逃避代谢应激的机制

项目编号： No.81502535

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： 林立

作者单位： 南方医科大学

项目金额： 18.5万元

中文摘要： 肿瘤细胞需消耗大量能量，当能量供不应求时发生代谢应激。目前尚不完全清楚肿瘤细胞如何抵抗代谢应激。上皮间质转化（EMT）被认为是上皮起源的肿瘤细胞转移的起始步骤，近期研究提示代谢应激可能引起EMT。我们曾分别报道了代谢应激激活MACC1、MACC1促进胃癌细胞EMT两项成果，但尚不明确它们之间的联系。我们预实验发现：代谢应激和MACC1下调DLC3表达，DLC3低表达的胃癌预后不良，沉默DLC3后胃癌细胞迁移侵袭增强。这提示MACC1/DLC3轴可能是调控代谢应激和EMT的重要信号，但目前DLC3的临床意义及生物学功能均鲜有报道。由此我们假设：代谢应激通过MACC1抑制DLC3引起胃癌细胞EMT，进而发生转移以逃避能量缺乏的微环境。本项目拟借助临床分析、动物及细胞功能实验、分子生物学实验等手段，围绕MACC1/DLC3轴对胃癌转移的作用开展研究，阐明胃癌细胞代谢应激和EMT之间的桥梁机制。

中文关键词： C07_胃肿瘤；上皮间质转化；代谢应激；肝癌缺失基因-3；结肠癌转移相关基因-1

英文摘要： Cancer cells consume large amount of energy. When energy demand exceeds supply, metabolic stress occurs. Currently, it remains largely unknown how cancer cells resist metabolic stress. It was recently reported that metabolic stress may induce epithelial-mesenchymal transition (EMT), which is the initial step of cancer metastasis. Our previous studies reported that metabolic stress activates Metastasis-associated in colon cancer-1 (MACC1), and MACC1 promotes EMT in gastric cancer (GC). However, the detailed associated mechanisms need further exploration. Our preliminary experiments suggest: 1) metabolic stress and MACC1 respectively suppressed Deleted in liver cancer-3 (DLC3) expression; 2) DLC3 low expression indicated adverse GC prognosis; 3) silencing DLC3 enhanced GC cell motility and invasiveness. These indicate that MACC1/DLC3 axis may be the link between metabolic stress and EMT. However, either the clinical significance or biological function of DLC3 is seldom studied. Therefore, we hypothesize that DLC3 is suppressed by MACC1 under metabolic stress, and hence EMT occurs and facilitates GC cells to escape from energy deficiency. Current project will be carried out by means of clinical analysis, animal and cellular experiments, and molecular biological experiments to explore the role of MACC1/DLC3 axis on GC metastasis. The results of this project will provide the connective mechanisms between metabolic stress and EMT in GC.

英文关键词： gastric cancer;epithelial-mesenchymal transition ;metabolic stress;DLC3;MACC1