Role of microRNAs in malignant progression

microRNA在恶性进展中的作用

• 批准号: 7638077
• 负责人: Li Ma
• 金额: $ 11.07万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638077
• 关键词: Accounting; Address; Alleles; Angiogenic Factor; Antibodies; Behavior; Biological Sciences; Biomedical Research; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; CDH1 gene; Cancer cell line; Cell Adhesion Molecules; Cells; Cessation of life; DNA Microarray Chip; Defect; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Distant Metastasis; Down-Regulation; E-Cadherin; Embryonic Development; Endocrine; Epithelial; Extracellular Matrix; Foundations; Functional RNA; Future; Gene Expression; Gene Targeting; Generations; Genetic; Goals; Growth Factor; Histologic; In Vitro; Institutes; Invaded; Investigation; Knockout Mice; Laboratories; Lead; Lung; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mentors; Mesenchymal; MicroRNAs; Micrometastasis; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Names; Neoplasm Metastasis; Oncogenic; Pathogenesis; Patients; Phase; Phenotype; Play; Postdoctoral Fellow; Primary Neoplasm; Principal Investigator; Production; Prognostic Marker; Proteins; Research; Role; Screening procedure; Stromal Cells; Technology; Testing; Therapeutic; TimeLine; Transgenic Mice; Tumor Angiogenesis; Tumor Cell Invasion; Up-Regulation; Vascular Endothelial Growth Factors; Work; Xenograft Model; angiogenesis; base; cancer cell; chemokine; cytokine; embryonic stem cell; homologous recombination; in vitro testing; in vivo; interest; loss of function; macrophage; malignant breast neoplasm; metastatic process; mouse model; mutant; neoplastic cell; outcome forecast; overexpression; preclinical study; prevent; programs; research and development; research study; transcription factor; tumor

DESCRIPTION (provided by applicant): It has become increasingly evident that cancer pathogenesis can involve a superfamily of small non-coding RNAs named microRNAs. While the oncogenic or tumor-suppressing functions of a number of microRNAs have been characterized, the role played by microRNAs in mediating metastasis was addressed only recently by work from our laboratory and several other groups. I am currently a Life Sciences Research Foundation Postdoctoral Fellow with the immediate goal of completing additional 1-2 years of mentored research with Dr. Bob Weinberg at the Whitehead Institute for Biomedical Research. In my initial screening, I identified three microRNAs that are most significantly upregulated in human breast cancer cell lines: miR-155, miR-9, and miR-l0b. Subsequently, I identified miR-l0b as a Twist-regulated microRNA that is highly expressed in metastatic cancer cells as well as in metastatic breast tumors from patients. This microRNA inhibits synthesis of the HOXD10 protein, permitting the expression of the pro-metastatic gene product, RhoC. Importantly, overexpression of miR-l0b in otherwise-non- metastatic breast cancer cells enables them to invade and metastasize in vivo. These findings represent the first functional evidence that overexpression of a microRNA can contribute to the development of metastasis. Since it remains unexplored whether targeting miR-l0b will inhibitmalignant progression, I now propose to combine genetic and pharmacological approaches to study miR-l0b loss-of-function effects in development and in breast cancer metastasis. Moreover, based on a previously undescribed observation that miR-l0b overexpression in the primary mammary tumor leads to lung macrophage accumulation prior to evidence of histologically detectable pulmonary micrometastases, I will explore the cell non-autonomous effects of miR-l0b in metastatic progression. In parallel, I will characterize the role of a second candidate microRNA that stood out in my initial screen, miR-9, in epithelial-mesenchymal transitions, angiogenesis, and metastasis, given that miR-9 is the only microRNA that is predicted to target E-cadherin, a major adhesion molecule whose loss is strongly implicatedin tumor invasion and metastasis. The long-term goal is to understand the role of microRNAs in regulating metastasis, and to develop new candidatetherapies for malignant diseases. RELEVANCE: Not only does this study illuminate the genetic and molecular basis of tumor metastasis, but it also has implications for breast cancer treatment. This will be the first proof-of-concept study of whether inhibiting a specific microRNA can prevent metastasis. Investigation of the cell non-autonomous effects of metastasis- mediating microRNAs may lead to discovery of endocrine proteins that have therapeutic potentials.

描述（由申请人提供）：越来越明显的是，癌症发病机理可以涉及一个名为microRNA的小型非编码RNA的超家族。尽管已经表征了许多microRNA的致癌性或肿瘤抑制功能，但仅最近我们的实验室和其他几个组的工作才解决了microRNA在介导转移中所起的作用。我目前是一名生命科学研究基金会博士后研究员，其直接目标是与怀特黑德生物医学研究所的鲍勃·温伯格（Bob Weinberg）博士完成1 - 2年的指导研究。在最初的筛查中，我确定了三个在人类乳腺癌细胞系中最显着上调的microRNA：miR-155，miR-9和miR-l0b。随后，我将miR-L0B鉴定为一种扭曲调节的microRNA，在转移性癌细胞以及患者的转移性乳腺肿瘤中高度表达。该microRNA抑制了HOXD10蛋白的合成，从而允许促异常基因产物的表达Rhoc。重要的是，其他非转移性乳腺癌细胞中miR-L0b的过表达使它们能够在体内侵入和转移。这些发现代表了第一个功能证据，即microRNA的过表达可以有助于转移的发展。由于靶向miR-L0b是否会抑制态度进展，我现在建议将遗传和药理学方法结合起来，以研究MiR-L0B功能丧失在发育和乳腺癌转移中的作用。此外，基于先前未描述的观察结果，即原发性乳腺肿瘤中的miR-L0b过表达导致肺巨噬细胞积累，然后在有组织学检测到可检测到的肺微转移的证据之前，我将探索MiR-L0B在转移性进展中miR-L0b的非自治作用。同时，我将表征第二个候选microRNA的作用，该候选microRNA在我的初始屏幕MiR-9中脱颖而出，在上皮 - 间质过渡，血管生成和转移中，鉴于MiR-9是唯一可以预测的MicroRNA，预计唯一一个靶向E-cadherin，是一种主要的粘附分子，其损失是强烈的tamor tumor tumor tamor tumor tumors tumor tamer tamer tumors tamer subiss and tumor tumors tumost tumost and tamer tamers tumasin tumasin tumasin tumasin tumasin tumasin tumasin tumasin tumasin。长期的目标是了解microRNA在调节转移中的作用，并为恶性疾病开发新的候选性疾病。 相关性：这项研究不仅可以阐明肿瘤转移的遗传和分子基础，而且对乳腺癌的治疗也有影响。这将是概念验证研究，即抑制特定的microRNA是否可以预防转移。对转移介导的microRNA的细胞非自主作用的研究可能导致发现具有治疗势的内分泌蛋白。