Role of the transcriptional corepressor TLE1 in the lung adenocarcinoma aggressiveness and progression

主要研究者/项目负责人（最后，第一，中间）：Biliran Jr.，赫克托 转录辅抑制因子TLE 1在肺腺癌侵袭性及预后中的作用 进展 摘要 肺腺癌（LUAD）占肺癌的近40%，其5年生存率为 只有15%是因为它的攻击性行为因此，迫切需要更好地了解分子 LUAD的发展和进展背后的事件。本实验室之前的R15研究已经证明 转录辅抑制因子TLE 1在LUAD细胞中发挥抗凋亡和EMT促进功能 从而增强它们的抗失巢凋亡性和体外锚定非依赖性生长， 体内肿瘤发生。从机制上讲，TLE 1的双重生存和EMT促进功能部分是由于 通过转录因子Zeb 1使肿瘤抑制因子E-钙粘蛋白基因转录沉默， 染色质修饰酶组蛋白脱乙酰酶（HDAC）。我们最近的生物信息学分析表明， TLE 1在LUAD中上调并显示不良预后价值。根据这些数据，我们 假设TLE 1调节促进存活和EMT的基因转录程序，以驱动 LUAD的侵略性和进展。为了验证这一假设，将实现以下具体目标： 解决：1）评估TLE 1在LUAD肿瘤发生和侵袭性中的功能作用; 2）分子 表征可能驱动LUAD进展的TLE 1介导的转录程序的组分; 和3）确定TLE 1核功能是否调节LUAD小鼠中的致瘤性和转移 异种移植模型。这些拟议的研究，这将是由本科研究生进行 与PI和研究助理一起，将推进我们对TLE 1转录的理解。 网络作为LUAD肿瘤发生的“驱动者”和作为减少LUAD的分子治疗靶点 侵略性 PHS 398（Rev. 5/01）页

Principal Investigator/Program Director (Last, first, middle): Biliran Jr., Hector Role of the transcriptional corepressor TLE1 in the lung adenocarcinoma aggressiveness and progression Abstract Lung adenocarcinoma (LUAD), which accounts for almost 40% of lung cancer, has a 5-year survival rate of only 15% due to its aggressive behavior. Hence, there is an urgent need to better understand the molecular events underlying the development and progression of LUAD. This lab's prior R15 work has obtained evidence that the transcriptional corepressor TLE1 exerts an anti-apoptotic- and EMT-promoting function in LUAD cells and thereby potentiating their anoikis resistance, and anchorage-independent growth in vitro as well as tumorigenesis in vivo. Mechanistically, the dual survival- and EMT-promoting function of TLE1 is in part due to its transcriptional silencing of the tumor suppressor E-cadherin gene via the transcription factor Zeb1 and chromatin modifying enzyme Histone deacetylase (HDAC). Our recent bioinformatics analyses indicate that TLE1 is upregulated and displays a poor prognostic value in LUAD. Based on these collective data, we hypothesize that TLE1 regulates a survival- and EMT-promoting gene transcription program to drive the aggressiveness and progression of LUAD. To test this hypothesis, the following specific aims will be addressed: 1) Evaluate the functional role of TLE1 in LUAD tumorigenesis and aggressiveness; 2) Molecularly characterize the components of the TLE1-mediated transcriptional program that may drive LUAD progression; and 3) Determine whether TLE1 nuclear function regulates tumorigenicity and metastasis in LUAD mouse xenograft models. These proposed studies, which will be performed by undergraduate research students together with the PI and a Research Assistant, will advance our understanding of the TLE1 transcriptional network as a “driver” of LUAD oncogenesis and as a molecular therapeutic target to curtail LUAD aggressiveness. PHS398 (Rev. 5/01) Page Continuation Format Page