A MicroRNA Cluster at 14q32 Drives Aggressive Lung Adenocarcinoma

• Published in: Clinical cancer research Vol. 20; no. 12; pp. 3107 - 3117
• Main Authors: NADAL, Ernest, JINJIE ZHONG, LIN, Jules, REDDY, Rishindra M, RAMNATH, Nithya, ORRINGER, Mark B, CHANG, Andrew C, BEER, David G, GUOAN CHEN
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.06.2014
• Subjects: Adenocarcinoma, Mucinous - genetics; Adenocarcinoma, Mucinous - mortality; Adenocarcinoma, Mucinous - secondary; Aged; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Carcinoma, Papillary - genetics; Carcinoma, Papillary - mortality; Carcinoma, Papillary - secondary; Case-Control Studies; Cell Movement; Chromosomes, Human, Pair 14 - genetics; Cluster Analysis; Cohort Studies; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Lung - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lymphatic Metastasis; Male; Medical sciences; MicroRNAs - genetics; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - mortality; Neoplasm Recurrence, Local - pathology; Neoplasm Staging; Pharmacology. Drug treatments; Pneumology; Prognosis; Survival Rate; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum; Lung disease; RNA interference; Respiratory disease; Lung cancer; Micro RNA; Chromosome D14; Cluster; Malignant tumor; Bronchopulmonary adenocarcinoma; Bronchopulmonary; Gene silencing; Bronchus disease; Cancer; High malignancy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-13-3348

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. 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. Unsupervised hierarchical clustering of 356 miRNAs identified 3 major clusters of lung AC correlated with stage (P = 0.023), tumor differentiation (P < 0.003), and IASLC histologic subtype of lung AC (P < 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. 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.