Abstract 3077: Dysregulation of microRNA-mRNA regulatory networks in the bronchial airway epithelium of smokers with lung cancer

Abstract

Abstract We have previously shown that gene expression alterations in cytologically normal epithelial cells from the bronchial airway can be used as an early detection biomarker for lung cancer in smokers. We hypothesize that bronchial epithelial expression of microRNAs, as regulators of gene expression, may also be affected by the presence of cancer and may regulate some of these gene expression differences. We propose a novel method to identify microRNAs functionally associated with disease that leverages the relationship between microRNA and mRNA expression by determining the differential connectivity (DC) of microRNA-mRNA association networks between disease and normal states. Bronchial epithelial brushes were collected from 220 former and current smokers who underwent bronchoscopy for suspicion of lung cancer (120 lung cancer patients and 100 healthy controls). For these subjects, we profiled microRNA expression via small RNA sequencing and gene expression via microarray. Each microRNA node is assigned a DC score, which captures the overall difference in the pairwise microRNA-gene correlation strengths between lung cancer and control subjects. We quantify the change in both the directionality and strength of the correlations between a microRNA and the gene nodes. Then, the observed DC scores are compared to the DC scores obtained with permuted class labels to identify microRNAs with signinficant disease-specific differences in microRNA-mRNA connectivity. The proposed DC method identifies 54 microRNAs which are significantly differentially connected in lung cancer cases compared to controls (FDR<0.1). Among the 54 microRNAs we find those previously associated with lung cancer, such as known dysregulated oncomirs, regulators of drug sensitivity to anticancer agents or targets for DNA methylation in non-small cell lung cancers. In addition, the genes that are significantly correlated with the DC microRNAs are enriched in cancer and immune system related pathways, such as membrane trafficking, apoptosis, mitotic cell cycle, hemostasis, FC gamma R mediated phagocytosis and signaling by Rho GTPases (FDR<0.1). We propose a novel approach for integrating microRNA and gene expression data to identify disease-associated changes in gene regulation by microRNAs and show that the microRNA-mRNA networks are significantly different between disease and normal states. These data suggest that changes in microRNA expression may drive some of the gene expression alterations observed in the cytologically normal epithelium from the proximal airway of patients with lung cancer and that airway microRNA-mRNA expression changes may ultimately serve as a biomarker for lung cancer detection. Citation Format: Ana Brandusa Pavel, Joshua D. Campbell, Gang Liu, Sherry Zhang, Hanqiao Liu, Lingqi Luo, Ji Xiao, Kate Porta, Duncan Whitney, Steven Dubinett, David Elashoff, Marc E. Lenburg, Avrum Spira. Dysregulation of microRNA-mRNA regulatory networks in the bronchial airway epithelium of smokers with lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3077. doi:10.1158/1538-7445.AM2015-3077