Data from A MicroRNA Cluster at 14q32 Drives Aggressive Lung Adenocarcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> To determine whether different subtypes of lung adenocarcinoma (AC) have distinct microRNA (miRNA) expression profiles, and to identify miRNAs associated with aggressive subgroups of resected lung AC.</p><p><b>Experimental Design:</b> miRNA expression profile analysis was performed in 91 resected lung AC and 10 matched nonmalignant lung tissues using a PCR-based array. An independent cohort of 60 lung ACs was used for validating by quantitative PCR the top 3 prognostic miRNAs. Gene-expression data from 51 miRNA profiled tumors was used for determining transcript-specific miRNA correlations and gene-enrichment pathway analysis.</p><p><b>Results:</b> Unsupervised hierarchical clustering of 356 miRNAs identified 3 major clusters of lung AC correlated with stage (<i>P</i> = 0.023), tumor differentiation (<i>P</i> < 0.003), and IASLC histologic subtype of lung AC (<i>P</i> < 0.005). Patients classified in cluster 3 had worse survival as compared with the other clusters. Eleven of 22 miRNAs associated with poor survival were encoded in a large miRNA cluster at 14q32. The top 3 prognostic 14q32 miRNAs (miR-411, miR-370, and miR-376a) were validated in an independent cohort of 60 lung AC. A significant association with cell migration and cell adhesion was found by integrating gene-expression data with miR-411, miR-370, and miR-376a expression. miR-411 knockdown significantly reduced cell migration in lung AC cell lines and this miRNA was overexpressed in tumors from patients who relapsed systemically.</p><p><b>Conclusions:</b> Different morphologic subtypes of lung AC have distinct miRNA expression profiles, and 3 miRNAs encoded at 14q32 (miR-411, miR-370, and miR-376a) were associated with poor survival after lung AC resection. <i>Clin Cancer Res; 20(12); 3107–17. ©2014 AACR</i>.</p></div>