MicroRNA Expression in Lung Cancer Development and Progression

描述（由申请人提供）：肺癌是这个国家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。在过去的二十年中，总体五年死亡率几乎没有变化。肺癌是一组异质性疾病，尽管形态相似，但其生长速度、转移潜力和对治疗的反应不同。新的靶向疗法，如表皮生长因子抑制剂（EGFR）（厄洛替尼和吉非替尼）在不同亚组肺癌患者中取得了成功。K-Ras存在于EGFR信号的下游，大约30%的非小细胞肺癌（腺癌）具有继发性突变的K-Ras激活。EGFR和K-Ras突变代表了非常不同的肺癌亚群，对化疗药物具有不同的敏感性和耐药模式，以及生存的潜在差异。K-Ras突变往往发生在前吸烟者或活跃吸烟者中，而EGFR突变在从不吸烟者中更为常见。MicroRNAs （miRNAs）是一类内源性小非编码rna（约21- 25nt长），在许多生物体中表达。mirna代表了一个新发现的基因调控层，通过靶向mRNA降解或抑制翻译。单个miRNA可以靶向数百个基因。mirna是基因调控、细胞凋亡、造血发育、细胞分化维持的组成部分，可能作为肿瘤抑制因子或癌基因发挥作用。我们建议采用一种多平台的方法，将microRNA表达和靶蛋白分析结合在K-Ras相关肿瘤发生的早期和晚期以及回归过程中，将确定筛选出的mirna，关键生物学途径和肺癌早期诊断和治疗的潜在靶点。我们的提议有两个具体目标：特异性目标1：使用K-Ras诱导的条件小鼠模型来定义在肿瘤起始、进展、建立和消退期间发生的miRNA表达的纵向模式；特异性目标2。通过利用高通量基因表达整合miRNA和mRNA表达模式，鉴定与K-Ras肺肿瘤发生相关的关键miRNA/target关系和生物学通路

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.