A MicroRNA cluster at 14q32 drives aggressive lung adenocarcinoma.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China ernestnadal@gmail.com dgbeer@umich.edu guoanche@med.umich.edu.
Ernest
E
Nadal
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, ChinaAuthors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China.
Jinjie
J
Zhong
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China.
Jules
J
Lin
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China.
Rishindra M
RM
Reddy
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China.
Nithya
N
Ramnath
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China.
Mark B
MB
Orringer
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China.
Andrew C
AC
Chang
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China ernestnadal@gmail.com dgbeer@umich.edu guoanche@med.umich.edu.
David G
DG
Beer
Authors' Affiliations: Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical School; Division of Medical Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; and Xinjiang Medical University, Xinjiang, China ernestnadal@gmail.com dgbeer@umich.edu guoanche@med.umich.edu.
Guoan
G
Chen
D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D016022:Case-Control Studies; D002465:Cell Movement; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D035683:MicroRNAs