Investigating the tumor suppressive functions of the miR-34 family of microRNAs

研究 microRNA 的 miR-34 家族的肿瘤抑制功能

• 批准号: 8528280
• 负责人: Carla P Concepcion
• 金额: $ 4.22万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528280
• 关键词: Address; Animals; Apoptosis; Attention; B-Cell Lymphomas; Biological Process; Caenorhabditis elegans; Cell Cycle Arrest; Cells; Characteristics; Chronic; Development; Disease; Dissection; Ectopic Expression; Family; Functional RNA; Genes; Genetic; Genetic Recombination; Goals; Growth; Human; In Vitro; Knockout Mice; Knowledge; Laboratories; Lung Adenocarcinoma; MYC gene; MYCN gene; Malignant Neoplasms; Mammals; Mediating; MicroRNAs; Modeling; Mus; Neuroblastoma; Oncogenic; Pathologic Processes; Pathway interactions; Physiological; Property; RNA Interference; Reporting; Role; System; Testing; Therapeutic; Therapeutic Intervention; Tissue Model; Tissues; Tumor Suppression; Tumor Suppressor Proteins; base; human cancer mouse model; in vivo; irradiation; member; mouse model; novel; prevent; promoter; public health relevance; research study; response; senescence; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are small, non-coding RNAs that act as post-transcriptional regulators. MicroRNA deregulation is a common feature of human cancers, and numerous miRNAs have oncogenic or tumor suppressive properties. The miR-34 family (miR-34a, miR-34b and miR-34c) has garnered much attention because it is directly regulated by p53 and can induce cell cycle arrest and apoptosis in vitro. Importantly, its inactivation has been observed in a number of human cancers. Despite the growing body of evidence suggesting its role as a tumor suppressor, most, if not all, previous studies on miR-34 have been done in vitro or using non-physiologic expression levels of miR-34, which are prone to artifactual results. Hence, its exact functions, mechanism and functionally relevant targets in vivo are still largely unknown. These gaps of knowledge prevent its exploitation for therapeutic intervention. The objective of this application is to investigate the physiologic and tumor suppressive properties of the miR-34 family. The central hypothesis is that members of the miR-34 family are important modulators of the p53 response, and are bona fide tumor suppressors. The proposal aims to answer the following questions: 1) Does chronic loss of miR-34 expression promote tumorigenesis in vivo? 2) What is the physiologic role of miR-34 in the p53 pathway? 3) Which p53 targets strongly cooperate with miR-34? To answer these questions, this application proposes to take advantage of constitutive and conditional knockout mice for the miR-34 family previously generated in our laboratory. Complete genetic inactivation of miR-34 function is compatible with viability in mammals, providing a unique opportunity to test the tumor suppressive properties of these miRNAs in a physiologic context. Initial results show that p53-dependent functions in miR-34-deficient mice and cells are intact, suggesting the functions of this miRNA family in the p53 pathway are likely redundant or highly context-specific. Thus, the experiments proposed in the first Aim of this application focus on two mouse models of human cancers wherein miR-34 loss has been described, while experiments under the second Aim seek to uncover redundancies between miR-34 and other p53 targets. The detailed understanding functions of members of the miR-34 family in normal and pathological processes that will emerge from the proposed study is a critical step towards not only exploring their tumor suppressive properties, but also developing novel anticancer strategies.

描述（由申请人提供）：MicroRNA (miRNA) 是小型非编码 RNA，充当转录后调节因子。 MicroRNA 失调是人类癌症的一个共同特征，许多 miRNA 具有致癌或肿瘤抑制特性。 miR-34家族（miR-34a、miR-34b和miR-34c）因其受p53直接调控并可在体外诱导细胞周期停滞和凋亡而备受关注。重要的是，其 已在多种人类癌症中观察到失活。尽管越来越多的证据表明其作为肿瘤抑制因子的作用，但大多数（如果不是全部）先前对 miR-34 的研究都是在体外进行的或使用 miR-34 的非生理表达水平，这很容易产生人为结果。因此，其确切的功能、机制和体内功能相关靶点仍然很大程度上未知。这些知识差距阻碍了其用于治疗干预的利用。本申请的目的是研究 miR-34 家族的生理和肿瘤抑制特性。核心假设是 miR-34 家族成员是 p53 反应的重要调节剂，并且是真正的肿瘤抑制因子。该提案旨在回答以下问题：1）miR-34表达的慢性丧失是否会促进体内肿瘤发生？ 2) miR-34 在 p53 通路中的生理作用是什么？ 3) 哪些 p53 靶点与 miR-34 密切合作？为了回答这些问题，本申请建议利用我们实验室先前生成的 miR-34 家族的组成型和条件敲除小鼠。 miR-34 功能的完全基因失活与哺乳动物的生存能力相一致，为在生理背景下测试这些 miRNA 的肿瘤抑制特性提供了独特的机会。初步结果表明，miR-34 缺陷小鼠和细胞中 p53 依赖性功能是完整的，这表明 p53 通路中该 miRNA 家族的功能可能是多余的或高度特定的。因此，本申请的第一个目标中提出的实验集中于两种人类癌症小鼠模型，其中已经描述了miR-34缺失，而第二个目标下的实验试图揭示miR-34和其他p53靶标之间的冗余。这项研究将详细了解 miR-34 家族成员在正常和病理过程中的功能，这不仅是探索其肿瘤抑制特性，而且是开发新型抗癌策略的关键一步。