Bit1 as a tumor suppressor and a therapeutic target in NSCLC

Bit1 作为肿瘤抑制因子和 NSCLC 的治疗靶点

基本信息

批准号：
8956867
负责人：
Hector Ramos Biliran
金额：
$ 42.76万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8956867
关键词：
A549 Affect Anchorage-Independent Growth Anoikis Apoptosis Apoptotic Biology Bypass Caspase Cell Death Cell Death Inhibition Cell Line Cell-Matrix Junction Cells Complex Cytoplasm DNA Binding Data Death Domain Disease Distant Down-Regulation E-Cadherin Enhancers Epithelial Epithelial Cells Exhibits Gene Targeting Genetic Grant Health Human In Vitro Investigation Knowledge Laboratories Lung Lung Neoplasms Malignant - descriptor Malignant Epithelial Cell Malignant neoplasm of lung Mesenchymal Mitochondria Mitochondrial Proteins Modeling Molecular Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nuclear Oncogenes Oncogenic Organ Pathogenesis Pathway interactions Phenotype Play Principal Investigator Proteins Recurrence Regulation Regulator Genes Reporting Research Resistance Role Structure of parenchyma of lung Testing Time Translations Tumor Suppressor Proteins Tumorigenicity Work Xenograft Model abstracting base cancer cell cell transformation chemotherapy combat in vivo inhibitor/antagonist lung tumorigenesis lung xenograft mortality novel novel therapeutic intervention novel therapeutics outcome forecast overexpression programs research study targeted delivery therapeutic target trait tumor tumor growth tumor progression tumorigenic undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Bit1 as a tumor suppressor and a therapeutic target in NSCLC Abstract The work in this laboratory supported by this grant in the past three years has made significant contributions to the field of Bit1 functional biology particularly in the contxt of anoikis resistance and tumorigenicity of Non- Small Cell Lung Carcinoma (NSCLC), a deadly and the most prevalent form of lung cancer. Bit1 is a mitochondrial protein that is released to the cytoplasm following of loss of cell attachment, and associates with the transcriptional regulator protein Amino-terminal Enhancer of Split (AES) to trigger caspase-independent apoptosis. Our studies have shown that NSCLC cells are likely to bypass this pathway to become anoikis resistant and anchorage independent and provide the first evidence of the tumor suppressive function of Bit1 in NSCLC. Importantly, our recent findings indicate that Bit1 in addition to its anoikis function may negatively regulate Epithelial Mesenchymal Transition (EMT) in NSCLC cells. Hence, the observed tumor suppressive function of Bit1 may relate to its dual role in promoting anoikis and inhibiting EMT. This novel EMT regulatory function of Bit1 underscores its potential utility to circumvent the aggressive and metastatic phenotype of NSCLC. In line with Bit1 as a lung tumor suppressor, the TLE1 corepressor, a sole known inhibitor of Bit1 function, has recently been identified as a lung specific oncogene. Our work has contributed to the elucidation on the mechanism of the TLE1 oncogenic pathway, in part through blocking the Bit1 apoptotic pathway and promoting EMT in NSCLC cells. Our collective data supports a model wherein Bit1 functions to turn off the survival- and EMT-promoting gene regulatory functions of TLE1 in an AES dependent manner. In continuation of this project, we will investigate our hypothesis that Bit1 is a suppressor of lung epithelial cell transformation in vitro and lung tumorigenesis and cancer metastasis in vivo through its inhibitory effect on the oncogenic TLE1 transcriptional program. To test the hypothesis, we propose the following specific aims: 1) to study the role of the Bit1/AES/TLE1 pathway in the malignant transformation of human lung epithelial cells, 2) to determine the mechanism underlying the formation and activity of the Bit1/AES complex and the regulation of the TLE1 gene regulatory functions by the Bit1-AES complex, and 3) to determine the effects of enhanced and suppressed Bit1 and/or TLE1 expression on tumorigenicity and metastasis of NSCLC in vivo. These proposed studies will advance the fundamental knowledge on the mechanism by which the Bit1 pathway regulates lung tumorigenesis and progression and will contribute to potential translation of this pathway in the treatment of lung cancer. PHS398 (Rev. 5/01) Page Continuation Format Page

DESCRIPTION (provided by applicable): Bit1 as a tumor suppressor and a therapeutic target in NSCLC Abstract The work in this laboratory supported by this grant in the past three years has made significant contributions to the field of Bit1 functional biology particularly in the contxt of anoikis resistance and tumorigenicity of Non- Small Cell Lung Carcinoma (NSCLC), a deadly and the most prevalent form of lung cancer. BIT1是一种线粒体蛋白，已释放到细胞质后造成细胞附着的丧失，并与分裂（AES）的转录调节蛋白氨基末端增强子（AES）相关，以触发与caspase无关的细胞凋亡。我们的研究表明，NSCLC细胞很可能绕过这一途径，使其成为耐药性和锚固独立性，并提供了NSCLC中BIT1抑制肿瘤功能的第一个证据。重要的是，我们最近的发现表明，除了其ANOIKIS功能外，BIT1可能会在NSCLC细胞中负调节上皮间质转变（EMT）。因此，观察到的BIT1的肿瘤抑制功能可能与其在促进Anoikis和抑制EMT中的双重作用有关。 Bit1的这种新型EMT调节功能强调了其潜在的效用，以规避NSCLC的侵略性和转移性表型。与BIT1作为肺肿瘤抑制剂一致，TLE1 Corepressor（一种已知的BIT1功能抑制剂）最近被确定为肺特异性癌基因。我们的工作有助于阐明TLE1致癌途径的机理，部分通过阻止BIT1凋亡途径并促进NSCLC细胞中的EMT。我们的集体数据支持一个模型，其中BIT1功能以AES依赖性方式关闭TLE1的生存和EMT促进基因调节功能。在继续该项目的持续下，我们将调查假设BIT1是通过其对Oncenitig基生石TLE1转录程序的抑制作用在体外和肺肿瘤发生和癌症转化和癌症转移的抑制。 To test the hypothesis, we propose the following specific aims: 1) to study the role of the Bit1/AES/TLE1 pathway in the malignant transformation of human lung epithelial cells, 2) to determine the mechanism underlying the formation and activity of the Bit1/AES complex and the regulation of the TLE1 gene regulatory functions by the Bit1-AES complex, and 3) to determine the effects of enhanced and suppressed Bit1 and/or NSCLC体内NSCLC的致瘤性和转移的TLE1表达。这些提出的研究将提高对BIT1途径调节肺部肿瘤和进展的机制的基本知识，并有助于该途径在治疗肺癌中的潜在翻译。 PHS398（Rev. 5/01）页面延续格式页面