Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related deaths for both sexes in industrialized countries [1, 2]
A significant association with cell migration and cell adhesion was found by integrating geneexpression 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
We found miRNAs differentially expressed among distinct morphologic subtypes of lung adenocarcinoma, which may have potential diagnostic utility in the future
Summary
Lung cancer is the leading cause of cancer-related deaths for both sexes in industrialized countries [1, 2]. Adenocarcinoma (AC) is the most common histologic subtype, accounting for about 40% of lung cancer diagnoses and 65,000 deaths each year in the United States. Lung AC is a heterogeneous disease and includes tumors with remarkably diverse clinical, pathologic, and molecular features. A new multidisciplinary lung AC classification has been recommended based on histopathology as well as clinical, Authors' Affiliations: 1Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; 2Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and 3Xinjiang Medical University, Xinjiang, China. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). According to the predominant histologic pattern, lung AC can be further classified in differentiated (comprising lepidic, invasive mucinous AC, acinar, papillary, and micropapillary) and undifferentiated/solid subtypes
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