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Deconstruction and in vivo functionalization of the ceRNA cancer network (PQ-11)

ceRNA癌症网络的解构和体内功能化（PQ-11）

基本信息

批准号：
8374041
负责人：
PIER PAOLO PANDOLFI
金额：
$ 36.11万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2012-09-18 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374041
关键词：
3&apos Untranslated Regions Address Alleles BRAF gene Biological Biology Cancer Biology Cells Code Development Dimensions Disease Foundations Functional RNA Gene Expression Profile Gene Expression Regulation Genes Genome Hand Human Human Genome In Vitro KRAS2 gene Knock-out Knockout Mice Language Light Luciferases Malignant Neoplasms Mammals Mediating Messenger RNA Methodology MicroRNAs Molecular Mus Mutation Oncogenes Oncogenic Organism PTEN gene Pathway interactions Phenotype Property Proteins Proto-Oncogenes Pseudogenes RNA Recurrence Regulation Regulator Genes Research Response Elements Role Series Testing Transcript Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated Regions Validation Yeasts base cancer genetics cancer type comparative drug discovery high throughput analysis in vivo innovation insight malignant phenotype mouse model novel overexpression theories tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): We have recently discovered a novel means of gene regulation whereby both protein-coding and non-coding RNAs are able to cross-talk through a new RNA language. In this new regulatory dimension, both protein-coding and non-coding RNAs (e.g. pseudogenes) can communicate with each other by competing for common microRNAs, hence acting as "competing endogenous RNAs" or ceRNAs. We have described several ceRNAs that regulate the tumor suppressor PTEN, thereby ascribing tumor suppressive functions to numerous cancer-unrelated mRNAs and non-coding RNAs. Moreover, we have developed a methodology to computationally predict ceRNAs for cancer-associated genes based upon the identity of their microRNA response elements (MREs), which are the foundation of this new language. This allows for the prediction and identification of novel putative tumor suppressors and oncogenes, and, critically, for the functionalization of the entire cancer-relevant transcriptome. We therefore propose to further characterize oncogenic and tumor suppressive ceRNA networks in vitro. Additionally, to explore the function of ceRNAs in basic biology in vivo, we have created a series of mouse models that express pseudogenes or 3'UTRs or lack established PTEN ceRNAs in an inducible manner. We will cross these mice to existing mouse models of cancer to characterize the contribution of ceRNAs to the malignant phenotype in vivo. We propose to address these outstanding questions pertaining to this new transformative biological dimension with the following specific aims: (1) to identify and functionally characteriz novel tumor suppressive PTEN ceRNAs as well as to analyze mouse models lacking bona fide PTEN ceRNAs such as ZEB2 and VHL; (2) to explore the effect of PTEN 3'UTR overexpression on the malignant phenotype elicited by either PTEN heterozygosity or overexpression of the PTEN targeting miR106b~25 cluster; (3) to analyze the ceRNA activity of the pseudogene BRAFps towards its ancestral gene, the proto-oncogene BRAF, in vitro and in vivo and its contribution to cancer development. We strongly believe that our application is both highly innovative and timely, with the potential to significantly further our understanding of this novel process of gene regulation in cancer genetics and biology. PUBLIC HEALTH RELEVANCE: We have recently discovered a novel mode of gene regulation that is based on a new competitive endogenous RNA (ceRNA) language. Protein-coding and non-coding ceRNAs can cross talk by competing for microRNAs, which constitute the words of the ceRNA language. On the basis of this new theory, we use computational predictions and experimental validation to unravel extensive regulatory networks that impact the expression of prominent cancer genes, thus adding numerous novel players to the list of putative tumor suppressors and oncogenes. This application outlines an experimental strategy to further characterize, in vivo, the ceRNA biological dimension, with specific focus on the ceRNA networks of the critical tumor suppressor PTEN and the proto-oncogene BRAF.

描述（由申请人提供）：我们最近发现了一种新的基因调控方法，蛋白质编码和非编码RNA都能够通过新的RNA语言进行交互。在这个新的调控维度中，蛋白质编码和非编码RNA（例如假基因）都可以通过竞争常见的microRNA来相互通信，因此充当“竞争性内源RNA”或ceRNA。我们已经描述了几种调节肿瘤抑制因子 PTEN 的 ceRNA，从而将肿瘤抑制功能归因于许多与癌症无关的 mRNA 和非编码 RNA。此外，我们还开发了一种方法，可以根据癌症相关基因的 microRNA 反应元件 (MRE) 的身份来计算预测 ceRNA，这是这种新语言的基础。这使得可以预测和鉴定新的假定肿瘤抑制因子和癌基因，并且至关重要的是，可以实现整个癌症相关基因的功能化。转录组。因此，我们建议在体外进一步表征致癌和肿瘤抑制 ceRNA 网络。此外，为了探索 ceRNA 在体内基础生物学中的功能，我们创建了一系列以诱导方式表达假基因或 3'UTR 或缺乏已建立的 PTEN ceRNA 的小鼠模型。我们将这些小鼠与现有的癌症小鼠模型进行杂交，以表征 ceRNA 对体内恶性表型的贡献。我们建议通过以下具体目标解决与这一新的变革性生物学维度相关的这些突出问题：（1）鉴定新型肿瘤抑制性 PTEN ceRNA 并进行功能表征，以及分析缺乏真正 PTEN ceRNA（例如 ZEB2 和 VHL）的小鼠模型； (2)探讨PTEN 3'UTR过表达对PTEN杂合性或PTEN靶向miR106b~25簇的过表达引起的恶性表型的影响； (3) 分析假基因BRAFps对其祖先基因原癌基因BRAF的体外和体内ceRNA活性及其对癌症发生的贡献。我们坚信，我们的应用既高度创新又及时，有可能显着加深我们对癌症遗传学和生物学中基因调控这一新过程的理解。公共健康相关性：我们最近发现了一种基于新的竞争性内源性 RNA (ceRNA) 语言的基因调控新模式。蛋白质编码和非编码 ceRNA 可以通过竞争构成 ceRNA 语言单词的 microRNA 进行交互。在这一新理论的基础上，我们利用计算预测和实验验证来揭示影响重要癌症基因表达的广泛调控网络，从而在假定的肿瘤抑制基因和癌基因列表中添加了许多新的参与者。本申请概述了进一步表征体内 ceRNA 生物学维度的实验策略，特别关注关键肿瘤抑制因子 PTEN 和原癌基因 BRAF 的 ceRNA 网络。