Regulation of metastasis and epithelial-mesenchymal transition by microRNAs

microRNA对转移和上皮间质转化的调节

基本信息

批准号：
8851531
负责人：
Li Ma
金额：
$ 32.79万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851531
关键词：
Accounting Address Affect Applications Grants Biochemical Biogenesis Biological Markers Breast Cancer Cell Breast Cancer Model Breast Carcinoma Breast Epithelial Cells Breast cancer metastasis Cancer Etiology Cell Adhesion Molecules Cells Cessation of life Clinical Computer Analysis Data Development Developmental Process Diagnosis Disease Distant Down-Regulation E-Cadherin Epithelial Evaluation Future Gene Targeting Genomic approach Goals High-Throughput RNA Sequencing Human Individual Investigation Knowledge Laboratories Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mediating Mesenchymal Messenger RNA Metastatic breast cancer MicroRNAs Molecular Molecular Genetics Molecular Profiling Mus Names Neoplasm Metastasis Oncogenic Pathogenesis Pathologic Processes Patients Play Primary Neoplasm Process Property Proteins RNA Sequence Analysis Regulation Reporting Research Research Subjects Role Site Stem cells Therapeutic Therapeutic Intervention Transcript Tumor Cell Invasion Untranslated RNA Up-Regulation Work base cancer cell cell type differential expression in vivo leukemia inhibitory factor receptor malignant breast neoplasm metastatic process miRNA expression profiling migration neoplastic cell novel novel strategies outcome forecast overexpression promoter receptor function research study therapeutic target transcription factor tumor tumor progression

Accounting Address Affect Applications Grants Biochemical Biogenesis Biological Markers Breast Cancer Cell Breast Cancer Model Breast Carcinoma Breast Epithelial Cells Breast cancer metastasis Cancer Etiology Cell Adhesion Molecules Cells Cessation of life Clinical Computer Analysis Data Development Developmental Process Diagnosis Disease Distant Down-Regulation E-Cadherin Epithelial Evaluation Future Gene Targeting Genomic approach Goals High-Throughput RNA Sequencing Human Individual Investigation Knowledge Laboratories Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mediating Mesenchymal Messenger RNA Metastatic breast cancer MicroRNAs Molecular Molecular Genetics Molecular Profiling Mus Names Neoplasm Metastasis Oncogenic Pathogenesis Pathologic Processes Patients Play Primary Neoplasm Process Property Proteins RNA Sequence Analysis Regulation Reporting Research Research Subjects Role Site Stem cells Therapeutic Therapeutic Intervention Transcript Tumor Cell Invasion Untranslated RNA Up-Regulation Work base cancer cell cell type differential expression in vivo leukemia inhibitory factor receptor malignant breast neoplasm metastatic process miRNA expression profiling migration neoplastic cell novel novel strategies outcome forecast overexpression promoter receptor function research study therapeutic target transcription factor tumor tumor progression

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项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand mechanisms of tumor progression and metastasis and to develop new approaches for molecularly targeted therapeutics. Metastasis, a multi-step process in which primary tumor cells disseminate to distant sites of the body and form secondary tumors, is the leading cause of cancer deaths and remains one of the most poorly understood pathological processes. New biomarkers of metastatic diseases and useful targets for therapeutic intervention, including proteins, microRNAs, and other non-coding RNAs, continue to be highly sought. We and others have demonstrated the existence of metastasis-promoting and metastasis-suppressing microRNAs. Moreover, we provided proof-of-concept evidence that antagomirs targeting a pro-metastatic microRNA can be efficiently delivered to fast growing tumor cells in vivo and can block metastasis formation by otherwise highly malignant cells. The molecular mechanisms by which these individual microRNAs function in metastatic progression warrant further investigation. In this application: 1) we will identify and characterize the functional targets of metastasis-promoting microRNAs. Combining high- throughput RNA sequencing, computational approach, functional experiments, mechanistic analysis, and patient studies, we will investigate a microRNA target that represents a novel suppressor of metastasis. 2) We will study how two distinct metastasis-regulating microRNAs are connected. Our preliminary data demonstrated that expression of a specific metastasis-promoting microRNA (miR-9) leads to downregulation of the primary transcript but upregulation of the mature form of another pro-metastatic microRNA (miR-10b). Subsequently, we will investigate the mechanisms by which miR-9 regulates miR-10b biogenesis and determine whether miR-10b is required for mediating miR-9-induced metastasis. 3) We will identify and characterize new epithelial-mesenchymal transition (EMT)-regulating microRNAs. By conducting microRNA expression profiling analysis of cells that have undergone EMT, we have recently identified a microRNA signature of EMT, and discovered that two microRNAs in this signature function as EMT inducers. We will determine the mechanisms by which these two microRNAs induce EMT and whether they regulate tumor metastasis and stem cell properties. The knowledge gained from these studies will fundamentally advance our current understanding of how microRNAs and their targets regulate metastasis and EMT and may have important clinical implications.

描述（由申请人提供）：我们的长期目标是了解肿瘤进展和转移的机制，并开发针对分子靶向疗法的新方法。转移是一种多步骤过程，其中原发性肿瘤细胞传播到人体的遥远部位并形成次要肿瘤，是癌症死亡的主要原因，仍然是最知名的病理过程之一。新的转移性疾病生物标志物和用于治疗干预的有用靶标，包括蛋白质，microRNA和其他非编码RNA，仍在高度寻求。我们和其他人已经证明了促进和转移抑制的microRNA的存在。此外，我们提供了概念证明的证据，表明靶向促次转移microRNA的Antagomirs可以在体内有效地输送到快速生长的肿瘤细胞中，并且可以通过高度恶性细胞来阻断转移的形成。这些单个microRNA在转移进展中起作用的分子机制需要进一步研究。在此应用程序中：1）我们将识别并表征促进转移的microRNA的功能目标。结合了高吞吐量RNA测序，计算方法，功能实验，机械分析和患者研究，我们将研究一个代表新型转移抑制剂的microRNA靶标。 2）我们将研究如何连接两个不同的转移调节的microRNA。我们的初步数据表明，特定转移的microRNA（miR-9）的表达导致主要转录本的下调，但上调另一种促次转移microRNA（miR-10b）的成熟形式的上调。随后，我们将研究miR-9调节miR-10b生物发生的机制，并确定是否需要miR-10b介导miR-9诱导的转移。 3）我们将识别并表征新的上皮 - 间质转变（EMT）调节microRNA。通过对经历EMT的细胞进行microRNA表达分析分析，我们最近确定了EMT的microRNA特征，并发现该签名功能中的两个microRNA作为EMT诱导剂。我们将确定这两个microRNA诱导EMT以及它们是否调节肿瘤转移和干细胞特性的机制。从这些研究中获得的知识将从根本上促进我们目前对microRNA及其目标如何调节转移和EMT的理解，并可能具有重要的临床意义。