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Stress and Proliferation States Impact MicroRNA-Mediated Regulation in Cancer

压力和增殖状态影响 MicroRNA 介导的癌症调节

基本信息

批准号：
8501813
负责人：
Phillip A Sharp
金额：
$ 45.97万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-14 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501813
关键词：
Adult Alleles Bibliography Binding Cancer Burden Cancer cell line Cell Survival Cells Cellular Stress DNA Damage Development Epitopes Family Generations Genes Goals Grant Haploidy Health Care Costs Homebound Persons Human Hypersensitivity Immunoprecipitation Individual Knock-out Link Malignant Neoplasms Mass Spectrum Analysis Mediating Messenger RNA MicroRNAs Missense Mutation Molecular Profiling Mus Mutate Mutation Nature Non-Small-Cell Lung Carcinoma Null Lymphocytes Oxygen Pathway interactions Phenotype Point Mutation Preparation Property Protein Binding Proteins Public Health Publications RNA Sequences Regulation Repression Research Ribonuclease III Role Signal Transduction Somatic Cell Stress System Testing Therapeutic Tissues Transcript Tumor Suppressor Proteins Up-Regulation Xenograft procedure arm base biological adaptation to stress blastomere structure cancer cell cancer therapy cell growth chemotherapy crosslink deprivation drug development embryonic stem cell endonuclease enhancing factor human DICER1 protein improved in vitro Model in vivo inhibitor/antagonist malignant phenotype mutant neoplastic cell novel therapeutics overexpression prevent public health relevance research study response sarcoma stressor therapy development tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): MicroRNAs are predicted to regulate a majority of genes in human cells and both overexpression and loss of expression of some miRNAs are correlated with malignant phenotypes in different cancer cells. A decrease in miRNA activity is most commonly observed and may be important for the plasticity of tumor cells to undergo transitions between differentiation states and to grow in different niches. One of the major objectives of this proposal is to investigate the functions of subsets of miRNAs in contributing to the properties of tumor cells and specifically to the ability of these cells to respond to stress. Many therapeutic treatments of cancer induce stress due to DNA damage, presence of unfolded proteins, deprivation of survival signals, and oxygen. We found that loss of miRNA regulation renders many types of cancer cells hypersensitive to such stress agents. For example, deletion of Dicer, a double strand endonuclease required for synthesis of most miRNAs, in many cancer cells yields viable cells that can in fact produce tumors in xenograft challenges but are hypersensitive to stress. Dicer- null human cancers have not been observed but recently sequencing of a haploid Dicer gene in several different types of human cancers identified a specific point mutation that inactivated one RNase III domain. This indicates that these tumor cells are being strongly selected for loss of a subset of miRNAs and for retention of other miRNAs. Cells expressing this mutant Dicer are defective for expression of the let-7 miRNA family but express near normal levels of other miRNAs. The four specific aims of this proposal build from progress over the past four years. First, we will further investigate the nature of factors targeting Argonaute 2 (Ago2) to specific RNA sequences in Dicer null cells. We will also investigate how this targeting enhances the quantitative level of silencing by co-binding miRNA. Second, we will characterize the subset of miRNAs generated by mutations of specific functions of Dicer and determine the consequences of expression of these subsets on tumor phenotype and response to stress. Third we will test if an inhibitor of Dicer should be considered as a promising objective for drug development to treat cancer in conjunction with chemotherapy. And fourth, we will investigate the function of Argonaute that is essential for viability in embryonic stem cells defective for synthesis of miRNAs, i.e. null for Dicer!" "

描述（由申请人提供）：MicroRNAs被预测调节人类细胞中的大多数基因，并且在不同的癌细胞中，一些MicroRNAs的过表达和表达缺失与恶性表型相关。miRNA活性的降低是最常见的观察结果，可能对肿瘤细胞的可塑性进行分化状态之间的转换和在不同的生态位中生长很重要。本提案的主要目标之一是研究mirna亚群在促进细胞凋亡方面的功能