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

转录辅阻遏物 TLE1 在肺腺癌侵袭性和进展中的作用

基本信息

批准号：
10409913
负责人：
Hector Ramos Biliran
金额：
$ 14.27万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10409913
关键词：
Address Adenocarcinoma Cell Affect Aggressive behavior Agreement Anchorage-Independent Growth Anoikis Apoptotic Automobile Driving Award Binding Bioinformatics Cancer Etiology Cell Line Cell Nucleus Cell membrane Cell-Matrix Junction Cessation of life ChIP-seq Chromatin Complex Cytoplasm Data Development Diagnosis Drug resistance E-Cadherin Enhancers Enzymes Epigenetic Process Epithelial Epithelial Cells Event Gene Expression Gene Silencing Genes Genetic Genetic Transcription Grant Growth Histologic Histone Deacetylase Human In Vitro Integrins Laboratories Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Mesenchymal Mitochondria Modeling Molecular Molecular Target Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nuclear Nuclear Translocation Oncogenes Oncogenic Patients Phenotype Principal Investigator Proteins Regulator Genes Research Assistant Resistance Role Signal Pathway Squamous cell carcinoma Stimulus Students Survival Rate Testing Transcriptional Regulation Transducin Transgenic Mice Tumor Suppressor Proteins Tumorigenicity Work Xenograft Model base bronchial epithelium cancer therapy chromatin remodeling druggable target epigenetic silencing gene network genetic corepressor in vivo inhibitor insight molecular targeted therapies mutant novel novel therapeutic intervention overexpression patient prognosis prognostic value programs promoter recruit therapeutic target transcription factor transcriptome sequencing tumor tumor progression tumorigenesis tumorigenic undergraduate research undergraduate student

项目摘要

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

首席研究员/计划主任（最后，第一，中间）：小比利兰，赫克托转录核心TLE1在肺腺癌侵略性和进展抽象的肺癌（LUAD）几乎占肺癌的40％，其存活率为5年由于其侵略性行为，只有15％。因此，迫切需要更好地理解分子 LUAD发展和发展的基础事件。该实验室的先前工作已获得证据转录核心TLE1在LUAD细胞中执行抗凋亡和EMT促进功能从而增强其抗厌氧菌性，并在体外与锚固无关的生长以及体内肿瘤发生。从机械上讲，TLE1的双重生存和EMT促进功能部分是由于它通过转录因子ZEB1和染色质修饰酶组蛋白脱乙酰基酶（HDAC）。我们最近的生物信息学分析表明， TLE1已更新，并在LUAD中显示出较差的预后价值。基于这些集体数据，我们假设TLE1调节生存和EMT促进基因转录程序以驱动 luad的侵略性和进步。为了检验这一假设，以下具体目标将是解决：1）评估TLE1在LUAD肿瘤发生和攻击性中的功能作用； 2）分子表征可能驱动luad进展的TLE1介导的转录程序的组件； 3）确定TLE1核功能是否调节Luad小鼠的肿瘤性和转移异种移植模型。这些拟议的研究将由本科研究专业的学生进行与PI和研究助理一起，将提高我们对TLE1转录的理解网络是LUAD肿瘤发生的“驱动力”，也是缩小LUAD的分子治疗靶标侵略性。 PHS398（Rev. 5/01）页面延续格式页面