The role of deubiquitinating enzyme USP33 in Slit-Robo signaling in lung cancer

描述（由申请人提供）：我们的长期目标是了解新型肿瘤抑制基因Slit和USP33的分子机制。我们之前的工作和初步数据表明，一种典型的神经元排斥物Slit是肺癌的重要肿瘤抑制因子，并且Slit的表达预示着肺癌患者更好的预后。为了剖析Slit信号通路并研究肺癌肿瘤抑制的机制，我们研究了信号转导分子如何与Slit受体Roundabout （Robo）相互作用。我们发现去泛素化酶USP33是肺癌中Slit-Robo信号通路的关键成分。本课题旨在结合动物模型和人类肺癌样本的序列分析，采用分子、生化和细胞生物学的方法，探讨Slit-Robo-USP33介导的肺癌肿瘤抑制作用。我们的试点深度测序研究支持了Slit-Robo- USP33通路的肿瘤抑制功能以及下游信号分子的参与。我们建立了体外实验和动物模型来研究这一新发现的肿瘤抑制通路在肺癌发展中的作用。我们计划利用这些综合的分子、细胞和遗传方法来确定Slit-Robo信号在抑制肺癌中的作用。我们的工作将有助于阐明Slit和USP33肿瘤抑制因子的分子机制，并确定Slit或USP33及其下游基因的遗传变异在人类肺癌发展中的作用。

DESCRIPTION (provided by applicant): Our long-term goal is to understand molecular mechanisms underlying novel tumor suppressor genes Slit and USP33. Our previous work and preliminary data suggest that a prototypical neuronal repellent, Slit, is an important tumor suppressor for lung cancer and that Slit expression predicts better prognosis in lung cancer patients. To dissect Slit signaling pathways and examine mechanisms underlying tumor suppression in lung cancer, we examined how signal-transducing molecules interacted with Slit receptor Roundabout (Robo). We identified the deubiquitinating enzyme, USP33, as a critical component in Slit-Robo signaling pathway(s) in lung cancer. This proposal aims to examine Slit-Robo-USP33 mediated tumor suppression in lung cancer using molecular, biochemical and cell biological methods in combination with animal models and sequence analyses of human lung cancer samples. Our pilot deep-sequencing studies support the tumor suppressive function of Slit-Robo- USP33 pathway and the involvement of the downstream signaling molecules. We have established both in vitro assays and animal models to study the role of this newly uncovered tumor suppression pathway in lung cancer development. We plan to use these integrated molecular, cellular and genetic approaches to define the role of Slit-Robo signaling in suppressing lung cancer. Our proposed work will help elucidate molecular mechanisms underlying Slit and USP33 tumor suppressors and determine the role of genetic variations in Slit or USP33 and their downstream genes in development of human lung cancer.