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

• 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
• 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

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

首席调查员/项目主任(最后、第一、中间)：小比利兰，赫克托 转录抑制因子TLE1在肺腺癌侵袭性和侵袭性中的作用 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发展和进展的基础事件。这个实验室之前的R15工作已经获得了证据 转录辅阻遏子TLE1在LUAD细胞中的抗凋亡和促EMT功能 从而增强它们的耐失巢能力，以及在体外的锚定非依赖性生长以及 体内的肿瘤发生。从机制上讲，TLE1的双重存活和EMT促进功能部分是由于 它通过转录因子ZEB1和转录因子抑制肿瘤抑制基因E-钙粘素基因的转录沉默 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 在LUAD中，TLE1表达上调，预后较差。根据这些收集的数据，我们 假设TLE1调节一个促进存活和EMT的基因转录程序，以驱动 LUAD的进攻性和进步性。为了验证这一假设，将实现以下具体目标 讨论：1)评估TLE1在LUAD肿瘤发生和侵袭性中的功能作用；2)分子生物学 描述可能驱动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小鼠的肿瘤发生和转移 异种移植模型。这些拟议的研究将由本科生进行 与PI和一名研究助理一起，将促进我们对TLE1转录的理解 网络是LUAD发生的“驱动力”，也是抑制LUAD的分子治疗靶点 咄咄逼人。 PHS398(5/01版)页面延续格式页面