MicroRNA Expression in Lung Cancer Development and Progression

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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.