NF2-AMOT信号传递在大肠癌中的功能及分子机制研究

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality in China, and the incidence of CRC grows significantly in recent years. The investigation of pathological mechanisms underlying CRC development, and identification of novel drug targets are vital for the control of CRC. The Hippo signaling pathway is involved in the development of multiple cancers, we have found that the expression levels of multiple Hippo pathway components are changed in CRC, with NF2 downregulated, whereas YAP and AMOTs upregulated. In cells, AMOTs ribosylation is decreased and protein stability is increased upon NF2 knockout. In addition, YAP phosphorylation appears increased when AMOTs genes are knocked out. Thus, NF2 deficiency in intestine may results in accumulation of AMOTs and YAP, which in turn lead to tumorigenesis. In this project, we will investigate the molecular mechanisms regulating NF2-AMOTs-YAP signal transduction, and reveal its role in the development of CRC.

大肠癌已成为中国第三大致死癌症,在所有恶性肿瘤中发病率上升速度最快,因此针对大肠癌发病机制的基础及转化研究急需加强。Hippo信号通路同肿瘤发生发展密切相关，通路成员中NF2是抑癌蛋白，而YAP是致癌蛋白。我们发现，在大肠腺癌样本中NF2表达降低而YAP表达上升；机制研究显示，NF2可以增强AMOTs核糖基化修饰从而降低AMOTs蛋白稳定性，AMOTs则能够促进YAP的功能。我们推测，NF2缺失通过上调AMOTs及YAP的表达水平或活性导致大肠癌发生。基于此猜想，本项目将利用细胞系、大肠癌临床样本、组织体外三维培养（类器官）及小鼠模型等技术手段，阐明NF2调节AMOTs及YAP的机制，揭示NF2在大肠癌中的病理功能，明确AMOTs及YAP在NF2缺失导致肠道肿瘤发生过程中的作用，并探讨相关机制在大肠癌早期诊断、预后判断及靶向治疗中的意义。

NF2抑癌基因在多种肿瘤中发生功能缺失性变异。在小鼠中遗传模型中， Nf2 敲除也会导致肿瘤发生。然而大部分NF2相关肿瘤都是良性肿瘤，细胞可能发展出不同策略应对NF2缺失带来的影响，导致肿瘤发展缓慢进行。我们发现NF2通过募集 E3 连接酶 RNF146 促进 Motin 家族蛋白 (Motins，包括AMOT， AMOTL1及AMOTL2) 的泛素化及蛋白质降解。在没有 NF2 的情况下，Motin显著积累、限制 YAP/TAZ 的过度激活、从而防止快速肿瘤发生。因此，NF2 缺乏不仅通过抑制 LATS1/2 激活 YAP/TAZ，并能够通过稳定 Motins 防止 YAP/TAZ 过度活化，该机制为 NF2 突变相关肿瘤良性性质提供了一种解释。围绕NF2及AMOT，本项目发表Cell Reports论文一篇，另外还有2篇血管新生及肿瘤浸润相关论文在投稿中。该项目的实施为深入理解NF2抑癌蛋白的分子调控机制提供了全新的见解。