抑制肿瘤转移的新靶点: iPLA2在整合素和基质金属蛋白酶再循环中的新颖作用

项目名称： 抑制肿瘤转移的新靶点: iPLA2在整合素和基质金属蛋白酶再循环中的新颖作用

项目编号： No.31671450

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 生物科学

项目作者： CHANG YONG CHUNG

作者单位： 天津大学

项目金额： 25万元

中文摘要： 癌症已经成为在中国死亡的主要原因之一，也成为了最重要的社会医疗问题。 然而 如何抑制肿瘤迁移、侵润和转移这一主要问题还远未解决。研究表明整合素和基质金属蛋白酶（MMPs）的过量表达与恶性肿瘤细胞的发展存在着密切的联系。尽管已有前人进行了针对整合素和MMPs的抑制剂设计，但却因为其具有细胞毒性而失败 。越来越多的研究证明了整合素和MMP再循环对于癌症转移的意义，但是如何对整合素再循环进行控制却鲜为人知。我们最近的研究揭示了钙非依赖性磷脂酶A2（iPLA2）的一项全新功能: iPLA2是c-Src和整合素再循环过程的特异性必要因素. 因而我们的首要目标是探究iPLA2如何控制αvβ3型整合素和 MT1-MMP再循环的细节机理，进而给予我们一条控制后两者运输的全新思路。我们将着眼于利用抑制iPLA2来阻断整合素或MMP的再循环，从而为阻断癌症转移的经济适用且低细胞毒性新途径的建立打下良好的基础。

中文关键词： 整合素(integrin)；基质金属蛋白酶（matrix；metalloproteinase）；肿瘤转移(metastasis)；钙非依赖型磷脂酶A2；再循环

英文摘要： With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. The migration of cancer cells away from the primary tumor into surrounding tissue is an important initial step in tumor progression. To date, the major challenge to the inhibition of migration, invasion and metastasis is far from being solved. Enhanced levels of expression of certain integrins and Matrix Metalloproteinases (MMPs), and a consequent increase in specific integrin signals, have been linked to cancer cell metastasis. Although there have been attempts to target integrins and MMPs directly using peptide or nonpeptide antagonist, they were not successful due to cytotoxicity resulted from essential nature of integrins and MMPs for normal cell function. As more evidences on the significance of integrin and MMP recycling in cancer metastasis were presented recently, there is very limited understanding toward ways of controlling integrin trafficking. Our recent studies revealed a novel function of Ca2+-independent phospholipase A2 (iPLA2) that is specifically required for the recycling of c-Src and integrin. This is consistent with recent observations that increased activity and expression of several PLA2 isoforms in various human cancers, suggesting their involvement in development and progression of tumor. A primary goal of this proposal is to understand mechanistic details of how iPLA2 controls the endocytic recycling of integrin αvβ3 and MT1-MMP, which would allow us to find a way to control their trafficking. Our approach to block integrin or MMP recycling by iPLA2 inhibition would give us an economically attractive and less cytotoxic therapeutic option for preventing tumor metastasis.

英文关键词： Integrin;Matrix Metalloproteinase;Metastasis;Ca2+-independent Phospholipase A2;Recycling