Ect2 Function in Lung Adenocarcinoma Initiation and Maintenance

 描述(申请人提供)：上皮细胞转化序列2(ECT2)已被鉴定为人类肿瘤中的癌基因。ECT2足以驱动成纤维细胞的转化，在多种肿瘤中过表达，是肿瘤细胞转化生长所必需的。然而，ECT2在肿瘤中发挥致癌活性的具体机制(S)目前尚不清楚。我们的初步研究表明：1)Ect2的全球环境基金活性和核定位是转化所必需的；2)Ect2与核仁蛋白上游结合因子1(UBF1)共定位并调节核糖体RNA(RRNA)的合成；3)Ect2的基因缺失在体内抑制Kras/P53介导的肺癌发生，并在体外抑制肺癌起始细胞(TIC)的生长。因此，我们假设：1)Ect2介导的rRNA转录对于肺腺癌(LADC)的转化是重要的；2)Ect2通过在体内维持肺TIC表型来驱动Kras/P53介导的LADC的形成。为了检验这些假说，本文提出了两个具体目标。在目标1中，我们将确定Ect2对rRNA转录的调控在LADC转化中的作用，在目标2中，我们将确定Ect2在LADC TICS体内致瘤性中的作用。这些目标的完成将有助于深入了解Ect2在TICS致瘤行为中的作用，增强我们对K-ras介导的肺肿瘤发生的启动事件的理解，以及如何在肿瘤细胞中调节核糖体生物合成的关键步骤rRNA合成以促进转化表型。

 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.