凋亡诱导因子AIF调控Wnt信号通路的机制研究

项目名称： 凋亡诱导因子AIF调控Wnt信号通路的机制研究

项目编号： No.81502001

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： 沈少明

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 新近研究表明，线粒体功能是肿瘤转移所必需的。我们发现，凋亡诱导因子（apoptosis-inducing factor，AIF）敲除的肿瘤细胞线粒体功能明显减弱, 但是转移能力却显著增强，且更易发生迁移和侵袭。另外，AIF低表达的结肠癌病人更易发生转移且生存期差。以上结果提示AIF敲除的肿瘤细胞中可能存在未知通路来克服线粒体功能缺陷对肿瘤转移的抑制作用。为了找到这一通路，我们在AIF敲除和过表达情况下对一系列转移相关基因进行了检测，结果发现AIF能够调控Wnt信号通路的活性及其一系列靶基因的表达。本课题将以这些重要发现为基础，明确Wnt信号通路在AIF和肿瘤转移之间的介导作用，并深入探寻AIF调控Wnt信号通路的分子机制。这些工作不仅可能为研究Wnt通路的分子机制提出新的观点和揭示AIF的新功能，并且可望为针对Wnt信号通路介导的肿瘤转移的药物靶点的发现提供新的线索。

中文关键词： 凋亡诱导因子；肿瘤转移；Wnt信号通路

英文摘要： Recently, mitochondria function has been reported to be essential for cancer metastasis. Knockdown of AIF in cancer cells significantly impaired mitochondrial oxidative phosphorylation. However, we found that AIF knockdown promoted the migration, invasion and metastasis of cancer cells. Moreover, low AIF in colon cancer patients correlates with poor survival and enhanced metastasis. These results indicate that AIF probably activated unknown pathway to overcome the inhibitory effect of mitochondrial deficiency on metastasis. To find this pathway, we detected the expression of a series of metastasis-related genes in AIF-knocked down and AIF-overexpressed cells, and found that the Wnt signaling pathway is most significantly regulated by AIF. Based on these original findings, in this project we will continue to confirm the role of activated Wnt signaling pathway in AIF knockdown induced metastasis, and figure out the mechanisms underlying the regulation of Wnt signaling pathway by AIF. Collectively, all these work would shed new sight for understanding the novel function of AIF and provide new mechanisms for Wnt signaling activation and metastasis.

英文关键词： AIF;cancer metastasis;Wnt signaling pathway