Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 1, Pages 349-364Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI82720
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Funding
- American Cancer Society-Kirby Foundations Fund Postdoctoral Fellowship [PF-13-088-01-CSM]
- National Cancer Institute (NCI) [R01CA177786, R03CA167695]
- Vanderbilt-Ingram Cancer Center Thoracic Program, Clinical and Translational Science Award from National Center for Advancing Translational Sciences [UL1TR000445]
- SPORE in Lung Cance [NCI P50CA090949]
- NCI Cancer Center [P30CA068485]
- NATIONAL CANCER INSTITUTE [T32CA119925, P50CA090949, R01CA177786, P30CA068485, R03CA167695] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000445] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR061474] Funding Source: NIH RePORTER
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MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
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