Ect2 Function in Lung Adenocarcinoma Initiation and Maintenance

 描述（由申请人提供）：上皮细胞转化序列2（Ect 2）已被鉴定为人类肿瘤中的癌基因。Ect 2足以驱动成纤维细胞的转化，在多种肿瘤中过表达，并且是肿瘤细胞转化生长所需的。然而，Ect 2在肿瘤中发挥其致癌活性的具体机制目前尚不清楚。我们的初步研究表明：1）Ect 2 GEF活性和核定位是转化所必需的，2）Ect 2与核仁蛋白上游结合因子1（UBF 1）共定位并调节核糖体RNA（rRNA）合成，3）Ect 2的遗传缺失抑制体内Kras/p53介导的肺肿瘤发生和体外肺肿瘤起始细胞（TIC）的生长。因此，我们假设：1）Ect 2介导的rRNA转录对于肺腺癌（LADC）转化是重要的，并且2）Ect 2通过在体内维持肺TIC表型来驱动Kras/p53介导的LADC形成。提出了两个具体的目标来测试这些假设。在目标1中，我们将确定Ect 2在LADC转化中调节rRNA转录的作用，在目标2中，我们将确定Ect 2在体内LADC TIC致瘤性中的作用。这些目标的完成将提供深入了解Ect 2在TIC的致瘤行为中的作用，增强我们对K-ras介导的肺肿瘤发生中的起始事件以及核糖体生物合成的关键步骤rRNA合成如何在肿瘤细胞中受到调控以促进转化表型的理解。

 DESCRIPTION (provided by applicant): Epithelial cell transforming sequence 2 (Ect2) has been identified as an oncogene in human tumors. Ect2 is sufficient to drive transformation in fibroblasts, is overexpressed in a variety of tumors and is required for transformed growth of tumor cells. However, the specific mechanism(s) by which Ect2 exerts its oncogenic activity in tumors are currently unknown. Our preliminary studies indicate that: 1) Ect2 GEF activity and nuclear localization are required for transformation, 2) Ect2 co-localizes with the nucleolar protein Upstream Binding Factor 1 (UBF1) and regulates ribosomal RNA (rRNA) synthesis, and 3) genetic loss of Ect2 inhibits Kras/p53-mediated lung tumorigenesis in vivo and growth of lung tumor initiating cells (TICs) ex vivo. Thus, we hypothesize that: 1) Ect2-mediated rRNA transcription is important for lung adenocarcinoma (LADC) transformation and 2) Ect2 drives Kras/p53-mediated LADC formation by maintaining a lung TIC phenotype in vivo. Two specific aims are proposed to test these hypotheses. In Aim 1 we will determine the role of Ect2 regulation of rRNA transcription in LADC transformation and in Aim 2 we will determine the role of Ect2 in the tumorigenicity of LADC TICs in vivo. Completion of these aims will provide insight into the role of Ect2 in the tumorigenic behavior of TICs, enhance our understanding of the initiating events in K-ras-mediated lung tumorigenesis and how a key step in ribosome biosynthesis, rRNA synthesis, may be regulated in tumor cells to promote the transformed phenotype.