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：
10627958
负责人：
Hector Ramos Biliran
金额：
$ 14.39万
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/10627958
关键词：
Address Adenocarcinoma Cell Affect Aggressive behavior Agreement Anchorage-Independent Growth Anoikis Apoptotic Automobile Driving Award Binding Bioinformatics Bite 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 Cells Epithelium 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 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 bronchial epithelium cancer therapy chromatin remodeling druggable target epigenetic silencing gene network gene repression 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/项目总监（最后、第一、中间）：Biliran Jr., Hector 转录辅阻遏物 TLE1 在肺腺癌侵袭性和侵袭性中的作用进展抽象的肺腺癌 (LUAD) 约占肺癌的 40%，其 5 年生存率为由于其攻击性行为，只有 15% 因此，迫切需要更好地了解该分子。该实验室之前的 R15 工作已经获得了 LUAD 发展和进展背后的事件证据。转录辅阻遏物 TLE1 在 LUAD 细胞中发挥抗凋亡和 EMT 促进功能并增强它们的失巢抵抗力以及体外和锚定独立生长从机制上讲，TLE1 的双重存活和 EMT 促进功能部分归因于它通过转录因子 Zeb1 抑制肿瘤抑制 E-钙粘蛋白基因的转录沉默我们最近的生物信息学分析表明，染色质修饰酶组蛋白脱乙酰酶 (HDAC)。 TLE1 在 LUAD 中表达上调并显示出较差的预后价值。 TLE1 调节促进生存和 EMT 的基因转录程序，以驱动 LUAD 的攻击性和进展为了检验这一假设，将实现以下具体目标。解决：1) 评估 TLE1 在 LUAD 肿瘤发生和侵袭性中的功能作用；2) 分子水平表征可能驱动 LUAD 进展的 TLE1 介导的转录程序的组成部分； 3)确定TLE1核功能是否调节LUAD小鼠的致瘤性和转移这些拟议的研究将由本科生进行。与 PI 和研究助理一起，将加深我们对 TLE1 转录的理解网络作为 LUAD 肿瘤发生的“驱动因素”和作为减少 LUAD 的分子治疗靶点攻击性。 PHS398（修订版 5/01）页面延续格式页面