Regulation of metastasis and epithelial-mesenchymal transition by microRNAs

microRNA对转移和上皮间质转化的调节

• 批准号: 8511590
• 负责人: Li Ma
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511590
• 关键词: Accounting; Address; Affect; Applications Grants; Biochemical; Biogenesis; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Breast Carcinoma; Cancer Etiology; Cell Adhesion Molecules; Cells; Cessation of life; Clinical; Computer Analysis; Data; Development; Developmental Process; Diagnosis; Disease; Distant; Down-Regulation; E-Cadherin; Epithelial; Epithelial Cells; Evaluation; Functional RNA; Future; Gene Targeting; Genomics; Goals; Human; Individual; Investigation; Knowledge; Laboratories; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Mediating; Mesenchymal; Messenger RNA; MicroRNAs; Molecular; Molecular Genetics; Molecular Profiling; Mus; Names; Neoplasm Metastasis; Oncogenic; Pathogenesis; Pathologic Processes; Patients; Play; Primary Neoplasm; Process; Property; Proteins; RNA Sequence Analysis; RNA Sequences; Regulation; Reporting; Research; Research Subjects; Role; Site; Stem cells; Therapeutic; Therapeutic Intervention; Transcript; Tumor Cell Invasion; Up-Regulation; Work; base; cancer cell; cell type; in vivo; leukemia inhibitory factor receptor; malignant breast neoplasm; metastatic process; migration; neoplastic cell; novel; novel strategies; outcome forecast; overexpression; promoter; receptor function; research study; therapeutic target; transcription factor; tumor; tumor progression

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，并开发分子靶向治疗的新方法。转移是一个多步骤的过程，其中原发性肿瘤细胞扩散到身体的远端部位并形成继发性肿瘤，是癌症死亡的主要原因，并且仍然是最不了解的病理过程之一。转移性疾病的新生物标志物和用于治疗干预的有用靶点，包括蛋白质、microRNA和其他非编码RNA，继续受到高度关注。我们和其他人已经证明了转移促进和转移抑制microRNA的存在。此外，我们提供了概念验证证据，证明靶向促转移microRNA的西洛米可以有效地递送到体内快速生长的肿瘤细胞，并且可以阻断否则高度恶性细胞的转移形成。这些单独的微小RNA在转移进展中发挥作用的分子机制值得进一步研究。在本申请中：1）我们将鉴定和表征促进转移的microRNA的功能靶标。结合高通量RNA测序、计算方法、功能实验、机制分析和患者研究，我们将研究代表新型转移抑制剂的microRNA靶标。2)我们将研究两种不同的转移调节microRNA是如何连接的。我们的初步数据表明，特定促进转移的微小RNA（miR-9）的表达会导致初级转录本的下调，但另一种促转移微小RNA（miR-10 b）的成熟形式的上调。随后，我们将研究miR-9调节miR-10 b生物合成的机制，并确定miR-10 b是否是介导miR-9诱导的转移所必需的。3)我们将确定和表征新的上皮间质转化（EMT）调节microRNAs。通过对经历EMT的细胞进行microRNA表达谱分析，我们最近鉴定了EMT的microRNA特征，并发现该特征中的两种microRNA作为EMT诱导剂发挥作用。我们将确定这两种microRNA诱导EMT的机制，以及它们是否调节肿瘤转移和干细胞特性。从这些研究中获得的知识将从根本上推进我们目前对microRNA及其靶点如何调节转移和EMT的理解，并可能具有重要的临床意义。