基于TGFβ/ALK5通路的托芬那酸抗肿瘤转移作用及机理研究

项目名称： 基于TGFβ/ALK5通路的托芬那酸抗肿瘤转移作用及机理研究

项目编号： No.81503098

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： 张小博

作者单位： 中国药科大学

项目金额： 17.9万元

中文摘要： 肿瘤细胞可以利用转化生长因子β（Transforming Growth Factor β, TGFβ）信号达到其侵袭转移的目的，因此成为近年来抗肿瘤转移的热点之一。我们前期研究首次发现非甾体抗炎药—托芬那酸能够抑制癌细胞中TGFβ/Smad信号通路，进而减弱癌细胞的上皮间质转化（EMT）进程和转移侵袭能力。初步机制研究表明，托芬那酸能够降低ALK5表达，从而抑制TGFβ/ALK5/Smad通路。但托芬那酸靶向TGFβ/ALK5通路进而发挥抗肿瘤转移活性的详细作用机制国内外文献尚未见报道。本项目拟采用免疫荧光、多聚核糖体谱分析、基因转染、显性失活突变技术等深入探讨托芬那酸调控ALK5表达的机理，应用ALK5稳定激活型细胞株和裸鼠肿瘤转移实验等技术验证抑制TGFβ/ALK5通路在托芬那酸抗肿瘤转移中的功能，最后综合分析评价托芬那酸的抗肿瘤转移机制，为临床抗肿瘤应用提供新的可选药物。

中文关键词： 肿瘤转移；TGFbeta信号通路；托芬那酸；分子靶点

英文摘要： It has been well documented that cancer cells may exploit to TGFβ’s advantage in terms of migration and invasion. Therefore, TGFβ signaling is an intriguing field into carcinogenesis research, and could be a potential target of drug development. We previously reported that tolfenamic acid (TA) suppressed TGFβ/Smad signal in different types of cancer cells, resulting in the disruption of TGFβ-induced EMT and metastasis. Further investigation found that TA could down-regulate ALK5 expression, causing the suppression of TGFβ/ALK5/Smad pathway. However, the molecular mechanism(s) by which TA targets TGFβ/ALK5 pathway and thus affects tumor metastasis is still unknown. In current project, we aim to demonstrate the detailed mechanisms of ALK5 expression regulation by TA via implying methods such as immunofluorescence, polyribosome profiling, gene transfection, dominate negative mutation, etc. We will further elucidate the role of TGFβ/ALK5 pathway in the inhibition of metastasis by TA using stable cell lines with constitutively active ALK5 form in vitro and in vivo. Finally, these studies will facilitate us to deeply understand the molecular mechanisms of tumor suppression by TA, which has great importance to its clinical application, and provides new evidence for its anti-tumor activity.

英文关键词： metastasis;TGFbeta signaling pathway;tolfenamic acid;molecular target