MicroRNA Expression in Lung Cancer Development and Progression

描述(申请人提供)：肺癌是这个国家最常见的癌症死亡原因，无论是男性还是女性。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，总的五年死亡率变化很小。肺癌是一组形态相似但生长速度、转移潜能和治疗反应不同的异质性疾病。新的靶向治疗，如表皮生长因子抑制剂(EGFR)(Erlotinib和Gefitinib)，已在不同的肺癌患者亚组中获得成功。K-RAS存在于EGFR信号的下游，大约30%的非小细胞肺癌(腺癌)存在K-RAS的继发性突变。EGFR和K-RAS突变代表了肺癌中非常不同的亚型，具有不同的化疗药物敏感性和耐药性模式，以及潜在的生存差异。K-RAS突变往往发生在既往吸烟者或经常吸烟者中，而EGFR突变更常见于从不吸烟者。MicroRNAs(MiRNAs)是一类在许多生物体中表达的内源性非编码小RNA家族(约21-25个核苷酸)。MiRNAs代表了新发现的一层基因调节层，它通过靶向mRNA来降解或抑制翻译。单个miRNA可能针对数百个基因。MiRNAs在基因调控、细胞凋亡、造血发育、维持细胞分化等过程中发挥着不可或缺的作用，可以作为肿瘤抑制因子或癌基因发挥作用。我们认为，在K-RAS相关肿瘤发生的早期和晚期，以及在回归过程中，结合microRNA表达和靶蛋白分析的多平台方法将识别选定的miRNAs，关键的生物学途径和早期诊断和治疗肺癌的潜在靶点。我们的建议有两个具体目标：特定目标1：使用K-RAS诱导的条件性小鼠模型来定义肿瘤发生、发展、建立和消退过程中miRNA表达的纵向模式和特定目标2.通过使用高通量基因表达整合miRNA和mRNA的表达模式来识别与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：在这个国家，肺癌是导致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外，了解疾病异质性的新分子方法，如microRNA图谱，将在我们与这种致命疾病的斗争中发挥重要作用。

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.