The Role of miRNAs in Epithelial-Mesenchymal Transition and Metastasis

miRNA 在上皮-间质转化和转移中的作用

基本信息

批准号：
8607149
负责人：
Yibin Kang
金额：
$ 30.96万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607149
关键词：
Animal Model Animals Biochemical Biological Assay Biological Models Breast Cancer Cell Breast Epithelial Cells Cancer cell line Candidate Disease Gene Cell Line Cessation of life Complex Data Disseminated Malignant Neoplasm Distant E-Cadherin Ectopic Expression Engineering Epithelial Epithelial Cells Family Gene Expression Profiling Gene Targeting Genes Genetic Genomics In Vitro Invaded Laboratories Lead Lesion Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Mass Spectrum Analysis Mediating Mesenchymal Metastatic to Methods Methyl-CpG-Binding Protein 2 MicroRNAs Molecular Mouse Mammary Tumor Virus Mus Neoplasm Metastasis New Agents Oncogenes Organ Pathologic Processes Phenotype Physiological Physiology Play Prevention Primary Neoplasm Process Proteomics Regulator Genes Research Role Site Staging Testing Therapeutic Tissues Transgenic Mice Validation Xenograft procedure epithelial to mesenchymal transition gene function improved in vivo in vivo Model inhibitor/antagonist insight interdisciplinary approach interest malignant breast neoplasm migration mouse model neoplastic cell novel overexpression public health relevance research study tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) have been increasingly recognized to play important roles in normal physiology and in pathological processes, including cancer. We recently identified the miR-200 family and the miR-194/192 cluster of miRNAs as negative regulators of epithelial-mesenchymal transition (EMT), which is thought to be the critical initiating step of cancer metastasis. These miRNAs maintain the epithelial cell phenotype and inhibit EMT by repressing the expression of transcriptional inhibitors of E-cadherin, including ZEB1/ZEB2 and MeCP2. Overexpression of these miRNAs inhibits TGF¿-induced EMT in normal mammary epithelial cells. Furthermore, ectopic expression of the EMT-related miRNAs in invasive breast tumor cells induces mesenchymal-epithelial transition (MET), the reverse process of EMT, with significant reduction of migration and invasion. Surprisingly, we also found that elevated miR-200 expression is correlated with increased ability of tumor cells to generate macroscopic lesions at secondary metastasis sites. These data in aggregate imply that there is a stage-specific role of these miRNAs in metastasis. Decreased miRNA expression in the primary tumor may stimulate EMT and subsequent dissemination of tumor cells, whereas increased miRNA expression will lead to MET and colonization of distant organs. As potentially new agents for anti-metastasis therapeutics, the functional role and molecular mechanism of these miRNAs in different stages of cancer progression require further characterization. We hypothesize that these miRNAs are critical master regulators of the transition between the epithelial and mesenchymal states of tumor cells and play important roles in both the initial invasion of primary tumors as well as metastatic colonization of secondary target organs. We will use a comprehensive approach to study the molecular mechanism of miRNA-mediated EMT and cancer metastasis, taking advantage of in vitro and in vivo models as well as genomic and proteomic research platforms available in our laboratory. To study the potential biphasic role of these miRNAs in metastasis, we will employ orthotopic and experimental metastasis assays. We will overexpress the miRNAs and modulate their downstream genes of interest in various mouse and human breast cancer cell lines and utilize in vivo animal models to investigate stage-specific effects on breast cancer metastasis (Aim 2). We will use combined analysis of gene expression profiling and mass spectrometry to identify novel target genes of EMT-related miRNAs and test the functional importance of these genes in EMT and metastasis using well-established in vitro and in vivo assays (Aim 2). Finally, we will evaluate the importance of EMT-related miRNAs in mammary gland function and mammary tumor progression using transgenic mouse models. We will generate MMTV transgenic mice for these miRNAs and test the role of these miRNAs in breast cancer progression in tumor-prone animals that overexpress the oncogene Neu or PyMT in their mammary tissue (Aim 3). Through these experiments, we will reveal the potential stage-specific roles and functional mechanisms for EMT-related miRNAs in cancer metastasis and provide important novel insights for improving the prevention and treatment of metastatic cancer.

描述：microRNA（miRNA）在正常的生理学中一直在乱七八糟的角色，并在逻辑过程中，包括癌症，我们最近确定了miR-200家族和miR-194/192 miRNA群他上皮细胞表型通过transssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss抑制E-钙粘蛋白mecp2抑制剂。 - 在正常的乳腺上皮细胞中引起的EMT。这些位置。这些miRNA在癌症的不同阶段的功能和分子机制需要进一步的表征。器官。我们将使用一种全面的方法来研究miRNA介导的EMT和癌症转移的分子机制，利用体外和体内模型以及我们实验室中的基因组和蛋白质组学研究平台。在转移中的这些miRNA中，我们将振奋和实验性转移测定法。我们将使用基因光谱法的联合分析来鉴定EMT相关的miRNA的靶基因，并使用良好的体外和体内测定（AIM 2）测试EMT转移中这些基因的F dementension（AIM 2），我们将评估EMT-相关的miRNA在乳腺功能和MMARY肿瘤程序中，我们将生成mmtv转基因小鼠用于miRNA，并测试这些miRNA在乳腺癌中的作用3）。