Regulation of Lung Cancer Metastasis by miR-200

miR-200对肺癌转移的调控

• 批准号: 8618869
• 负责人: Jonathan M Kurie
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-14 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618869
• 关键词: Adenocarcinoma Cell; Alleles; Area; Binding; Biomedical Engineering; Biopsy Specimen; Blood Coagulation Factor VII; Breast Cancer Model; Cancer Etiology; Cancer Patient; Cause of Death; Cell Shape; Cells; Cellular biology; Cessation of life; Clinical Trials; Country; Disease; Early treatment; Epithelial; Event; Family; Family member; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Human; Individual; Injection of therapeutic agent; Investigation; Ligands; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Metastasis Suppression; MicroRNAs; Modeling; Mus; Neoplasm Metastasis; Oncogenic; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Primary Neoplasm; Process; Property; Public Health; Recurrence; Regulation; Reporting; Resected; Role; Signal Transduction; Small RNA; Staging; Techniques; Transcription Repressor/Corepressor; Transfection; Transforming Growth Factors; Tumor Cell Line; Tumor Suppressor Proteins; Tumorigenicity; base; cancer cell; epithelial to mesenchymal transition; expression vector; extracellular; high risk; inhibitor/antagonist; innovation; matrigel; metastasis prevention; mouse model; mutant; neoplastic cell; notch protein; novel strategies; prevent; promoter; public health relevance; response; secretase; small hairpin RNA; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Our goal is to better understand the biologic basis for lung cancer metastasis, which could potentially have a tremendous public health impact because lung cancer is the primary cause of cancer-related death in Western countries, and metastasis is the primary cause of death from lung cancer. On the basis of our previous reports, we believe that the extracellular signals that repress microRNA-200 (miR-200) levels in lung cancer cells are key drivers of metastasis and are targets for metastasis prevention. Here we show that metastasis-prone tumor cells from mice that develop lung adenocarcinomas owing to expression of mutant K-ras and p53 express both Notch and Notch ligands, and the Notch ligand jagged2 promotes tumor sphere formation, EMT, invasion, and metastasis. Jagged2 increases the expression of all six GATA transcription factor family members, and GATA3 promotes tumor cell EMT and metastasis by suppressing miR-200 levels. We posit that each of the GATA factors regulated by jagged2 plays a distinct transcriptional role and collectively mediate the diverse biologic effects of jagged2 in this tumor model. This hypothesis is innovative because it links the Notch axis to a microRNA that is central to EMT and metastasis, and it opens a new area of investigation into the role of GATA factors as promoters, rather than repressors, of metastasis. The experimental approaches we have proposed are innovative; the mouse model is based on one we created that closely recapitulates biologic and transcriptional features of human lung adenocarcinoma, and the cell micropatterning techniques we have developed are at the forefront of the interface between bioengineering and cell biology. We propose two Specific Aims. The first Aim is to determine whether inactivation of Jagged2 abrogates metastasis in a mouse model of lung adenocarcinoma. For this Aim, we will create mice that conditionally inactivate jagged2 and express oncogenic K-ras and p53 in the lung; we will examine whether jagged2/Notch-dependent interactions between tumor cells are required for polarized sphere formation and EMT using cell micro-patterning techniques we have developed; and we will determine whether high jagged2 levels correlate with low microRNA-200 family member expression in human lung adenocarcinoma biopsy samples and whether this expression pattern correlates with disease recurrence and short duration of survival. The second Aim is to examine whether the GATA transcription factor family members up-regulated by jagged2 are required for tumor cell polarization, sensitivity to TGF2-induced EMT, and metastasis. For this Aim, we will use genetic approaches to deplete GATA factors individually from lung adenocarcinoma cells; we will study the biologic and transcriptional properties of those cells in culture; and we will examine their tumorigenicity and metastatic potential in an orthotopic lung tumor model we have developed. Our long-term goal is to develop novel approaches to identify those patients who are at high risk for recurrence following treatment of early-stage disease and to use pharmacologic approaches to target key mediators of metastasis in those patients.

描述（由申请人提供）：我们的目标是更好地了解肺癌转移的生物学基础，因为肺癌是西方国家与癌症相关死亡的主要原因，这可能会产生巨大的公共卫生影响，而转移是肺癌死亡的主要原因。根据我们先前的报告，我们认为肺癌细胞中抑制microRNA-200（miR-200）水平的细胞外信号是转移的关键驱动因素，并且是预防转移的靶标。在这里，我们表明，由于突变K-RAS和p53的表达，来自小鼠的转移性肿瘤细胞出现了肺腺癌，表达了Notch和Notch配体，而Notch配体JAGGED2促进了肿瘤球体的形成，EMT，入侵和转移。 JAGGED2增加了所有六个GATA转录因子家族成员的表达，而GATA3通过抑制miR-200水平来促进肿瘤细胞EMT和转移。我们认为，由Jagged2调节的每个GATA因子都起着独特的转录作用，并在此肿瘤模型中共同介导了JAGGED2的不同生物学效应。该假设具有创新性，因为它将缺口轴连接到对EMT和转移至关重要的microRNA，并且为GATA因子作为转移的启动子而不是压抑剂的作用开辟了一个新的研究领域。我们提出的实验方法是创新的。小鼠模型是基于我们创建的，该模型密切概括了人类肺腺癌的生物学和转录特征，而我们开发的细胞微图技术是生物工程和细胞生物学之间界面的最前沿。我们提出了两个具体目标。第一个目的是确定Jagged2的灭活是否会消除肺腺癌小鼠模型中的转移。为了这个目标，我们将创建有条件地灭活jagged2并在肺中表达致癌的K-Ras和p53的小鼠。我们将使用我们开发的细胞微观图解技术来检查肿瘤细胞之间的锯齿状2/Notch依赖性相互作用。我们将确定高锯齿状2水平是否与人类肺腺癌活检样本中的microRNA-200族成员表达低相关，以及这种表达模式是否与疾病复发和短期生存时间相关。第二个目的是检查肿瘤细胞极化，对TGF2诱导的EMT和转移的敏感性所需的GATA转录因子家族成员是否需要jagged2上调。为此，我们将使用遗传方法从肺腺癌细胞中分别耗尽GATA因子。我们将研究这些细胞在培养中的生物学和转录特性。我们将在我们开发的正常肺部肿瘤模型中检查它们的肿瘤性和转移性潜力。我们的长期目标是开发新的方法，以识别那些在治疗早期疾病后患有高风险的患者，并使用药理学方法来针对这些患者转移的关键介体。