MicroRNA Expression in Lung Cancer Development and Progression

肺癌发生和进展中的 MicroRNA 表达

• 批准号: 7873350
• 负责人: SERGE PATRICK NANASINKAM
• 金额: $ 16.58万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-05 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873350
• 关键词: Adenocarcinoma; Animals; Apoptosis Regulation Gene; Biological; Cancer Etiology; Cancer Patient; Cell Differentiation process; Cessation of life; Country; Development; Disease; Early Diagnosis; Epidermal Growth Factor; Erlotinib; Exhibits; Family; Functional RNA; Gefitinib; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genome; Growth; 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; public health relevance; response; tumor; tumor initiation; tumorigenesis

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最常见的原因。 2009年，估计有236,000例新病例和163,000例死亡。在过去的二十年中，总五年死亡率发生了很小的变化。肺癌代表了一组异质性疾病，尽管形态相似，但表现出不同的生长速率，转移性潜力和对疗法的反应。新的靶向疗法，例如表皮生长因子抑制剂（EGFR）（Erlotinib和Gefitinib）在肺癌患者的不同亚组中已经成功。 K-RAS从EGFR信号传导下游存在，大约30％的非小细胞肺癌（腺癌）携带了继发于突变的K-RAS激活。 EGFR和K-RAS突变代表了肺癌的非常不同的亚组，具有不同的敏感性和对化学治疗剂的抗性以及生存的潜在差异。 K-RAS突变往往发生在以前或活跃的吸烟者中，而EGFR突变在永不吸烟者中更为常见。 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）的家族。 miRNA通过靶向mRNA来降解或抑制翻译，代表了新发现的基因调节层。单个miRNA可能靶向数百个基因。 miRNA是基因调节，凋亡，造血发育，维持细胞分化的组成部分，并且可能充当肿瘤抑制剂或癌基因。 我们提出，在K-RAS相关的肿瘤发生以及回归期间，一种融合了microRNA表达和靶蛋白分析的多平台方法将确定精选的miRNA，关键的生物学途径和潜在的肺癌早期诊断和治疗的潜在靶标。我们针对我们的提案有两个具体的目的：具体目的1：使用有条件的K-RAS诱导鼠模型来定义miRNA表达的纵向模式，这些模式在肿瘤的启动，进展，建立和回归过程中发生，以及特定的目标2。通过使用高吞吐量基因的使用，使用高吞吐量的基因表达来整合表达的miRNA和靶标关系，以识别key mirna/tarm tum tum tum kirna/tum tum k ras k-ras k-ras k-ras k-ras k-ras 公共卫生相关性：肺癌是男性和女性中最常见的癌症死亡原因。 2009年，估计有236,000例新病例和163,000例死亡。这导致了巨大的社会和经济负担。因此，除了进行烟草戒烟和更有效的早期检测手段的积极性计划外，在我们与这种致命疾病的斗争中，新型的分子方法（例如microRNA分析）将很重要。