MicroRNA Expression in Lung Cancer Development and Progression

肺癌发生和进展中的 MicroRNA 表达

基本信息

批准号：
8021770
负责人：
SERGE PATRICK NANASINKAM
金额：
$ 19.3万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-05 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8021770
关键词：
Adenocarcinoma Animals Apoptosis Regulation Gene Biological Cancer Etiology Cancer Patient Cell Differentiation process Cessation of life Country Development Disease Early Diagnosis Early treatment Epidermal Growth Factor Erlotinib Exhibits Family Functional RNA Gefitinib Gene Expression Gene Expression Regulation Gene Proteins Genes Genome Growth Health Hematopoietic Heterogeneity In Vitro Label Lung Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Messenger RNA MicroRNAs Modeling Molecular Morphology Mus Mutation Non-Small-Cell Lung Carcinoma Oncogenes Organism Pathway interactions Pattern Plant Viruses Protein Analysis Proteins Research Resistance Screening procedure Secondary to Signal Transduction Smoker Solid Subgroup Tobacco Use Cessation Transgenic Model Translations Tumor Suppressor Proteins Woman chemotherapeutic agent high risk inhibitor/antagonist lung tumorigenesis mRNA Transcript Degradation men mortality novel programs response tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the most frequent cause of cancer deaths in this country for both men and women. In 2009, 236,000 new cases and 163,000 deaths are estimated. The overall five year mortality has changed very little in the last two decades. Lung cancer represents a group of heterogeneous diseases that despite similar morphology exhibit different growth rates, metastatic potential and response to therapies. New targeted therapies such as epidermal growth factor inhibitors (EGFR) (Erlotinib and Gefitinib) have been successful in distinct subgroups of lung cancer patients. K-Ras exists downstream from EGFR signaling and approximately 30% of non-small cell lung cancers (adenocarcinomas) harbor K-Ras activation secondary to mutations. EGFR and K-Ras mutations represent very distinct subgroups of lung cancers with differing patterns of sensitivity and resistance to chemotherapeutic agents as well as potential differences in survival. K-Ras mutations tend to occur in former or active smokers while EGFR mutations are more common in never smokers. MicroRNAs (miRNAs) are a family of endogenous, small non-coding RNAs (approximately 21-25 nt long) expressed in many organisms. MiRNAs represent a newly discovered layer of gene regulation by targeting mRNA for degradation or inhibition of translation. A single miRNA may target several hundreds of genes. MiRNAs are integral to gene regulation, apoptosis, hematopoietic development, the maintenance of cell differentiation and may function as either tumor suppressors or oncogenes. We propose that a multi-platform approach that incorporates microRNA expression and target protein analysis both early and late in K-Ras related tumorigenesis as well as during regression will identify select miRNAs, critical biological pathways and potential targets for early diagnosis and treatment of lung cancer. We have two specific aims to our proposal: Specific Aim 1: Use a conditional murine model of K-Ras induction to define longitudinal patterns of miRNA expression that occur during tumor initiation, progression, establishment and regression and Specific Aim 2. Through the use of high throughput gene expression integrate miRNA and mRNA patterns of expression to identify key miRNA/target relationships and biological pathways that are relevant to K-Ras lung tumorigenesis PUBLIC HEALTH RELEVANCE: Lung cancer is the most frequent cause of cancer deaths in this country for both men and women. In 2009, 236,000 new cases and 163,000 deaths are estimated. This has resulted in tremendous societal and financial burden. Therefore, in addition to aggressive programs for tobacco cessation and more efficacious means of early detection, novel molecular approaches to understanding disease heterogeneity such as microRNA profiling will be important in our battle against this deadly disease.

描述（由申请人提供）：肺癌是该国男性和女性癌症死亡的最常见原因。 2009 年，估计有 236,000 例新病例和 163,000 例死亡。过去二十年中，总体五年死亡率变化很小。肺癌代表一组异质性疾病，尽管形态相似，但表现出不同的生长速度、转移潜力和对治疗的反应。表皮生长因子抑制剂 (EGFR)（厄洛替尼和吉非替尼）等新的靶向疗法已在肺癌患者的不同亚组中取得了成功。 K-Ras 存在于 EGFR 信号传导下游，大约 30% 的非小细胞肺癌（腺癌）存在继发于突变的 K-Ras 激活。 EGFR 和 K-Ras 突变代表了非常不同的肺癌亚组，它们对化疗药物的敏感性和耐药性不同，而且生存率也存在潜在差异。 K-Ras 突变往往发生在以前或活跃的吸烟者中，而 EGFR 突变在从不吸烟者中更常见。 MicroRNA (miRNA) 是在许多生物体中表达的内源性小非编码 RNA（大约 21-25 nt 长）家族。 miRNA 代表了新发现的基因调控层，它通过靶向 mRNA 进行降解或抑制翻译。单个 miRNA 可能靶向数百个基因。 miRNA 是基因调控、细胞凋亡、造血发育、细胞分化维持不可或缺的组成部分，并且可以作为肿瘤抑制基因或癌基因发挥作用。我们提出一种多平台方法，将 K-Ras 相关肿瘤发生的早期和晚期以及回归过程中的 microRNA 表达和靶蛋白分析结合起来，将识别出选定的 miRNA、关键生物学途径和肺癌早期诊断和治疗的潜在靶点。我们的提案有两个具体目标：具体目标 1：使用 K-Ras 诱导的条件小鼠模型来定义肿瘤发生、进展、建立和消退期间发生的 miRNA 表达的纵向模式；具体目标 2。高通量基因表达整合 miRNA 和 mRNA 表达模式，以确定与 K-Ras 肺肿瘤发生相关的关键 miRNA/靶点关系和生物学途径公共卫生相关性：肺癌是该国男性和女性癌症死亡的最常见原因。 2009 年，估计有 236,000 例新病例和 163,000 例死亡。这造成了巨大的社会和财政负担。因此，除了积极的戒烟计划和更有效的早期检测手段之外，了解疾病异质性的新分子方法（例如 microRNA 分析）对于我们对抗这种致命疾病也很重要。