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Role of microRNAs in genetic mouse models of pancreatic cancer

microRNA在胰腺癌遗传小鼠模型中的作用

基本信息

批准号：
7750587
负责人：
Murray Korc
金额：
$ 13.91万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750587
关键词：
Affect Alleles Anchorage-Independent Growth Animals Apoptosis Biological Markers CDKN2A gene Cancer Biology Cancer Etiology Cancer cell line Cancerous Carcinoma Cell Line Cell physiology Cells Cellular Assay Cessation of life Clinical Collection Development Diagnosis Dicer Enzyme Disease Progression Early Diagnosis Enzymes Epigenetic Process Exhibits Exploratory/Developmental Grant Functional RNA Gene Expression Gene Targeting Generations Genes Genetic Genotype Heterogeneity Human In Situ Hybridization In Vitro Incidence Individual Intraepithelial Neoplasia Knock-in Mouse Lesion Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating MicroRNAs Modeling Molecular Molecular Profiling Mus Mutate Mutation Northern Blotting Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Patients Plasmids Porifera Process Regulation Regulator Genes Regulatory Pathway Reporting Resistance Role Signal Pathway Specimen Staging Subfamily lentivirinae Suggestion System TP53 gene Testing Therapeutic Therapeutic Agents Time Transgenes Transgenic Animals Transgenic Organisms Tumor Suppressor Genes Tumor Tissue United States Ursidae Family base cancer cell cell type chemotherapy combinatorial genetic manipulation genome-wide human DICER1 protein locked nucleic acid loss of function loss of function mutation mortality mouse model neoplastic cell new therapeutic target novel novel therapeutics outcome forecast overexpression pancreatic tumorigenesis public health relevance research study response tool tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. Because of its stubborn resistance to chemotherapy, there is an urgent need to develop novel therapeutic strategies for this deadly cancer. Numerous studies have revealed an important etiological contribution of activated mutations of K-ras and loss of function mutations of p16, p53 and Smad4. Mouse models that combine mutations in these genes have permitted their study specifically in the context of the pancreas thanks to the Cre/LoxP system. However, the potential role of other regulatory pathways, either with respect to the development of PDAC and/or in relation to the genesis of its marked chemoresistance, has not been thoroughly investigated. MicroRNAs (miRNAs) are a new class of short non-coding RNA genes [10-12], which act as post- transcriptional negative regulators of gene expression [13]. MiRNA-mediated regulation of tumorigenesis is emerging as a new paradigm in the field of cancer biology. The large number of predicted target genes for each miRNA suggests that miRNAs could provide a novel and global mechanism to modulate gene expression comparable to genome-wide epigenetic and transcriptional changes associated with cancer. Moreover, several reports indicate that specific miRNAs exhibit functions reminiscent of tumor suppressors and oncogenes. In addition, global decreases in miRNA activity by loss of Dicer or other enzymes required for miRNA processing result in enhanced tumorigenic potential, reflecting on the overall role of miRNAs in mediating tumor suppressive functions. Our preliminary studies and reports from other groups have linked a subset of miRNAs to PDAC based on: 1) their differential expression in pancreatic cell lines and/or in clinical specimens and/or 2) their interaction with signaling pathways etiologically relevant such as K-Ras, p16 and p53. Thus, miRNAs could serve as useful biomarkers for early detection, diagnosis and/or prognosis, advance our understanding of the molecular mechanisms of tumorigenesis, and serve as novel therapeutic targets. Based on these observations, our overall hypothesis is that miRNAs exert a crucial role in the initiation and progression of PDAC and that combinatorial therapy with current therapeutic agents and synthetic modulators of this novel class of regulatory RNAs may provide an effective strategy to increase patient response to treatment. We have established several transgenic murine strains that bear conditional mutations in K-ras and/or p16 genes, the most frequently mutated genes in PDAC, and we propose to conduct a functional analysis of miRNAs aimed at assessing: 1) The effect of decreased global miRNA activity in disease progression by crossing a conditional loss of function dicer1floxed/floxed animal to cancer-prone animals bearing mutated alleles of K-ras and/or p16 genes. 2) The contribution of individual miRNAs to pancreatic tumorigenesis in vitro by manipulating levels of miRNA expression/activity in murine and human pancreatic cancer cell lines. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy in which mortality virtually equals incidence, yet for which there are no satisfactory therapeutic treatments. Emerging evidence suggests a pivotal role of microRNAs in cancer biology. We hypothesize that combinatorial therapy of current chemotoxic compounds and synthetic modulators of this novel class of regulatory RNAs may provide an effective strategy to increase patient response to treatment. In this proposal, we will investigate the etiological contribution of microRNAs to PDAC and conduct a preliminary assessment of their potential therapeutic application.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是美国癌症死亡的第四大原因。由于其对化疗的顽固抵抗，迫切需要为这种致命的癌症开发新的治疗策略。许多研究表明K-ras基因的激活突变和p16、p53和Smad 4基因的功能缺失突变在病因学上起着重要作用。由于Cre/LoxP系统，在这些基因中联合收割机突变的小鼠模型允许他们在胰腺的背景下进行专门的研究。然而，其他调节途径的潜在作用，无论是相对于PDAC的发展和/或其显着的耐药性的起源，尚未得到彻底的研究。微小RNA（miRNAs）是一类新的短的非编码RNA基因[10-12]，其充当基因表达的转录后负调控因子[13]。miRNA介导的肿瘤发生调节正在成为癌症生物学领域的新范式。每种miRNA的大量预测靶基因表明，与与癌症相关的全基因组表观遗传和转录变化相比，miRNA可以提供一种新型的全球机制来调节基因表达。此外，一些报告表明特定的miRNA表现出令人想起肿瘤抑制因子和癌基因的功能。此外，由于Dicer或miRNA加工所需的其他酶的损失而导致的miRNA活性的总体降低导致了增强的致瘤潜力，反映了miRNA在介导肿瘤抑制功能中的总体作用。我们的初步研究和来自其他小组的报告已经将一个miRNA子集与PDAC联系起来，其基于：1）它们在胰腺细胞系和/或临床标本中的差异表达和/或2）它们与病因学相关的信号传导途径如K-Ras、p16和p53的相互作用。因此，miRNAs可以作为早期检测、诊断和/或预后的有用生物标志物，促进我们对肿瘤发生的分子机制的理解，并作为新的治疗靶点。基于这些观察，我们的总体假设是，miRNA在PDAC的起始和进展中发挥关键作用，并且使用当前治疗剂和这类新型调节RNA的合成调节剂的组合疗法可能提供增加患者对治疗的反应的有效策略。我们已经建立了几种转基因小鼠品系，它们在K-ras和/或p16基因（PDAC中最常见的突变基因）中携带条件突变，我们建议对miRNAs进行功能分析，旨在评估：1）通过将条件性功能丧失dicer 1floxed/floxed动物与携带突变的K-ras和/或K-ras等位基因的癌症易感动物杂交，整体miRNA活性降低在疾病进展中的作用。或p16基因。2)通过操纵小鼠和人胰腺癌细胞系中的miRNA表达/活性水平，体外研究单个miRNA对胰腺肿瘤发生的贡献。公共卫生相关性：胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，其死亡率几乎等于发病率，但没有令人满意的治疗方法。新出现的证据表明microRNA在癌症生物学中的关键作用。我们假设，目前的化学毒性化合物和这种新型调节RNA的合成调节剂的组合治疗可能提供一种有效的策略，以增加患者对治疗的反应。在这项提案中，我们将研究microRNA对PDAC的病因学贡献，并对其潜在的治疗应用进行初步评估。