Notch3信号通路对透明细胞性肾细胞癌生物学行为调控的机制研究

项目名称： Notch3信号通路对透明细胞性肾细胞癌生物学行为调控的机制研究

项目编号： No.81202011

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 陈旭

作者单位： 中山大学

项目金额： 24万元

中文摘要： 肾癌是泌尿系统常见肿瘤，对药物治疗不敏感且预后不良。探索其发生发展的分子机制，寻找更有效的分子诊疗靶点一直是该领域的研究热点。Notch3信号通路过度激活是多种恶性肿瘤形成发展中重大的分子事件。在前期工作中我们发现Notch3在透明细胞性肾细胞癌（CCRCC）中高表达，对其沉默可显著抑制肿瘤生长，表明其重要性。我们还通过染色质免疫沉淀芯片发现参与多种肿瘤侵袭转移的TIAM1可能是Notch3下游靶基因之一。本课题中，我们将以探索Notch3在CCRCCs中的作用机制为目标，利用逆转录病毒载体在细胞和裸鼠肾原位移植瘤模型中高表达Notch3胞内活性段来研究该通路对CCRCCs发生发展的生物学作用。同时运用表达相关性分析、EMSA、启动子荧光素酶表达实验等论证TIAM1为Notch3下游靶基因。从而阐明Notch3信号通路对CCRCCs生物学行为调控的分子机制，为诊疗提供新思路。

中文关键词： Notch3；肾癌；上皮间质转化；；

英文摘要： Renal cell carcinoma (RCC) constitutes the majority of urological neoplasms, which is insensitive to chemotherapy and presents a poor clinical outcome. Exploration of the molecular mechanisms will help unveil more effective therapeutic targets and is an important topic currently being investigated by many groups around the world. Previous study has demonstrated that up-regulation of the Notch3 signaling pathway plays a key role in the pathogenesis of many tumors development and progress. Our results show Notch3 is up-regulated in clear cell RCC (CCRCC) as well. Meanwhile, silencing of the Notch3 suppresses tumor cell proliferation. This indicates Notch3 may play an important role in CCRCCs. By performing a ChIP-on-chip, we were also able to elucidate series of other downstream target genes such as TIAM1，which has been implicated to involve in the metastasis of many cancers.In this project,we will further investigate the mechanism of Notch3 in CCRCCs, by ways of over-expressing its intracellular domain in both cell lines and orthotopic-transplant nude mice model via retrovirus. We will also validate TIAM1 as a de novo downstream of Notch3 pathway by series of experiments such as Expression correlation,EMSA, Promoter Luciferase Assay etc. Taken together, we expect to discover the mechanism of Notch3's regulation

英文关键词： Notch3；renal cancer；EMT；；