AQP1参与TGF-β诱导肿瘤上皮间质转化及调控网络研究和化合物ZX-1201的作用及机制

项目名称： AQP1参与TGF-β诱导肿瘤上皮间质转化及调控网络研究和化合物ZX-1201的作用及机制

项目编号： No.81473235

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李学军

作者单位： 北京大学

项目金额： 85万元

中文摘要： 肿瘤细胞通过上皮间质转化（EMT）而增强自身的迁移和浸润能力，TGF-β是EMT的主要诱导者。AQPs是多种肿瘤生长的生物标志物，并影响肿瘤的转移和肿瘤细胞的迁移，AQP1是否参与肿瘤的EMT过程及其调节机制尚未见报道。我们的前期研究发现来自于泽泻的单体化合物ZX1201能明显逆转TGF-β1诱导的肿瘤EMT过程，并通过抑制AQP1和TGF-β1的表达和功能而抑制肿瘤细胞的迁移。本课题拟探讨AQP1在TGF-β1诱导的肿瘤EMT以及肿瘤生长和转移中的角色；研究TGF-β1自我激活的机制及其下游事件与AQP1的关系，包括TGF-β1/Smad/ AP1、Notch/ Gata3、Six1/ miR106b-25/TGF-β1对AQP1的调节；构建扩展的网络，确定调节该网络的关键节点；研究ZX1201对上述途径和网络的作用，优化ZX1201的结构，为发展抗肿瘤及肿瘤转移的新药提供线索和思路。

中文关键词： 抗肿瘤；分子机制；调控网络；抗肿瘤药物；肿瘤转移

英文摘要： Through epithelial-mesenchymal transformation (EMT), the tumor cells enhance their capacity of migration and invasion, TGF-β play an important role on EMT process. In a variety of malignancies, the AQPs are biomarkers on certain kinds of tumors and have been recognized as one of the targets on anticancer drugs discovery. Our recent study revealed a compound ZX-1201 from Alisma could significantly reverse TGF-β1 and EGF-induced tumor cell EMT and their migration by inhibition of AQP1 and TGF-β1 expression. This proposed study intend to explore the role of AQP1 on TGF-β1 induced EMT and tumor growth and metastasis. And observe the effects of ZX-1201 and its derivatives. We will focuses on the possible mechanisms of TGF-β1 on its self activation and its downstream events, to clarify the possible relationship with AQP1. We will study TGF-β1 / Smad / AP1, Notch / Gata3, Six1 / miR106b-25/TGF-β1 pathways on AQP1 regulation and EMT and tumor metastasis. To examine ZX-1201 compounds on regulating these networks and validate the possible targets, provide clues for the development of new drugs on anti-tumor and anti-tumor metastasis.

英文关键词： anti-tumor;molecular mechanism;regulative network;anti-cancer drugs;tumor metastasis