The role of microRNA in oncogene-induced senescence and cancer development

microRNA在癌基因诱导的衰老和癌症发展中的作用

基本信息

批准号：
9071400
负责人：
PEIQING SUN
金额：
$ 32.16万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9071400
关键词：
Applications Grants Binding Bypass CDKN2A gene CHD7 gene California Cancer Model Cell Aging Cell physiology ChIP-seq Collaborations Defense Mechanisms Development Dominant-Negative Mutation Down-Regulation Due Process Genes Genetic Screening Genetic Transcription Grant Health Human Knowledge Malignant Neoplasms Mammalian Cell Mammals Mediating MicroRNAs Modeling Mus Oncogene Activation Oncogenes Oncogenic Pathologic Processes Physiological Processes Process RNA-Binding Proteins Reporter Reporting Role Sampling Signal Transduction Skin Carcinogenesis Testing Transcription Coactivator Transgenic Mice Translational Repression Tumor Suppression Universities Untranslated RNA Up-Regulation Work cancer therapy carcinogenesis defense response dimethylbenzanthracene genome-wide in vivo insight knock-down mRNA Transcript Degradation metaplastic cell transformation novel overexpression promoter protein expression senescence targeted cancer therapy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): microRNA (miRNA) is a class of small non-coding RNAs that suppress the expression of protein-encoding genes via translational repression and/or mRNA degradation. Studies indicate that miRNAs act as global regulators of cellular functions, through their involvement in a wide range of physiological and pathological processes including cancer development. In a genetic screen, we found that miR-30, a miRNA frequently overexpressed in cancer, disrupts a critical tumor suppressing mechanism called oncogene-induced senescence. Further studies demonstrated that miR-30 disrupts oncogenic ras-induced senescence by directly targeting CHD7, a transcriptional co-activator, and TNRC6A, an RNA-binding protein essential for miRNA functionality. In this grant application, we will investigate te mechanisms underlying the roles of CHD7 and TNRC6A in miR-30-mediated bypass of oncogenic ras-induced senescence, and examine the impact of the miR-30-CHD7/TNRC6A regulatory circuit on cancer development in vivo. In Aim 1, we will investigate the hypothesis that CHD7 acts as a transcriptional coactivator to induce the transcription of a key senescence effector p16INK4A, and that by suppressing CHD7, miR-30 inhibits ras-induced p16INK4A expression and hence senescence induction. Alternative approaches are proposed to perform ChIP-seq analysis to systematically identify additional direct transcriptional targets of CHD7 involved in senescence. In Aim 2, the hypothesis will be tested that by suppressing TNRC6A, miR-30 globally down-regulates the functionality of miRNAs, which in turn leads to disruption of ras-induced senescence. In Aim 3, we will analyze the effect of miR-30 on senescence induction and cancer development in vivo using miR-30 transgenic mice and a mouse cancer model. In addition, the expression levels of miR-30, CHD7 and TNRC6A will be determined in human tumor samples, in order to establish that miR-30 contributes to human cancer development by suppressing its direct targets CHD7 and TNRC6A. Studies proposed in this grant will provide mechanistic insights into the novel function of miR-30 in oncogene-induced senescence. Through analyses of these miR-30 targets, we will identify novel mechanisms and novel signaling components that mediate oncogene-induced senescence and tumor suppression, which will offer new opportunities for cancer therapies targeting cellular senescence.

描述（由申请人提供）：microRNA（miRNA）是一类小型非编码RNA，可通过翻译抑制和/或mRNA降解来抑制蛋白质编码基因的表达。研究表明，miRNA通过参与包括癌症发展在内的广泛的生理和病理过程，是细胞功能的全球调节剂。在遗传筛选中，我们发现miR-30是一种在癌症中过度过表达的miRNA，破坏了一种称为癌基因诱导的衰老的关键肿瘤抑制机制。进一步的研究表明，miR-30通过直接靶向转录共激活剂CHD7和TNRC6A（一种RNA结合蛋白对于miRNA功能必不可少的RNA结合蛋白）来破坏致癌性RAS诱导的衰老。在此赠款应用中，我们将研究CHD7和TNRC6A在miR-30介导的致癌性RAS诱导的衰老的旁路中的作用的TE机制，并检查MiR-30-CHD7/TNRC6A调节回路对体内癌症发展的影响。在AIM 1中，我们将研究CHD7充当转录共激活因子的假设，以诱导关键衰老效应p16Ink4a的转录，并且通过抑制CHD7，miR-30抑制了RAS诱导的P16INK4A表达和衰老诱导。提出了替代方法来执行CHIP-SEQ分析，以系统地确定涉及衰老的CHD7的其他直接转录靶标。在AIM 2中，将检验该假设，即通过抑制TNRC6A，miR-30在全球范围内下调miRNA的功能，这又导致RAS诱导的衰老破坏。在AIM 3中，我们将使用miR-30转基因小鼠和小鼠癌模型分析miR-30对体内衰老诱导和癌症发展的影响。此外，将在人类肿瘤样品中确定miR-30，CHD7和TNRC6A的表达水平，以确定miR-30通过抑制其直接靶标CHD7和TNRC6A来促进人类癌症的发展。该赠款中提出的研究将提供有关miR-30在致癌基因诱导的衰老中的新功能的机械见解。通过对这些miR-30靶标的分析，我们将确定介导癌基因诱导的衰老和肿瘤抑制的新型机制和新型信号传导成分，这将为靶向细胞衰老的癌症疗法提供新的机会。