Abstract 2013: Integrative genomic studies pertaining to cigarette smoke and human lung carcinogenesis

Abstract

Abstract Lung cancer is a major cause of cancer deaths worldwide. Whereas the vast majority of these neoplasms are directly attributable to cigarette abuse, the molecular mechanisms contributing to tobacco- associated pulmonary carcinogenesis are not well understood. In the present study, we utilized microarray techniques and systems biology analysis to investigate global mRNA and microRNA (miRNA) expression profiles during lung cancer progression using an in-vitro model. Four sets of cell lines were chosen to examine miRNA/mRNA signatures during lung cancer progression, including primary normal human bronchial epithelia (NHBE) as well as small airway epithelial cells (SAEC), immortalized human bronchial epithelial cells (HBEC), a lung cancer line (H1975) derived from a non-smoker, and three lung cancer lines (H1299, Calu-6 and A549) derived from smokers. Cells were cultured in normal media (NM) with or without cigarette smoke condensate (CSC), the DNA demethylating agent, 5 aza-2’ deoxycytidine (DAC), and the histone deacetylase inhibitor Depsipeptide (DP) to examine how cigarette smoke and epigenetic events may affect global mRNA and miRNA expression during pulmonary carcinogenesis. Based on global mRNA/miRNA expression clustering, primary respiratory epithelial cells, immortalized HBEC, and smoker as well as non-smoker derived lung cancer lines were readily distinguished from one another. Each cell group exhibited its own special set of miRNAs /mRNAs, which were over or under-expressed relative to primary cells. Comparison of miRNA profiles in CSC-treated vs untreated NHBE, SAEC, HBEC, A549 and Calu-6 cells revealed that cigarette smoke induces over-expression of miR-21 and miR-31. MiR-21 and miR-31 were also significantly over-expressed in smoker-derived A549 and Calu-6 lung cancer cells relative to non-smoker-derived H1975. In addition, differential gene expression profiles were observed in smoker-derived vs non-smoker derived lung cancer cells. A group of miRNAs/ mRNA were preferentially modulated by sequential DAC/DP treatment in these cultured cells. Further analysis of differentially expressed miRNAs/mRNAs observed in this model system may provide new insight regarding molecular mechanisms associated with pulmonary carcinogenesis, and reveal novel biomarkers for lung cancer diagnosis and prognosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2013.