MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer.

Edmonds MD, Boyd KL, Moyo T, Mitra R, Duszynski R, Arrate MP, Chen X, Zhao Z, Blackwell TS, Andl T, Eischen CM
J Clin Invest. 2016 126 (1): 349-64

PMID: 26657862 · PMCID: PMC4701567 · DOI:10.1172/JCI82720

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.

MeSH Terms (15)

Adenocarcinoma Adenocarcinoma of Lung Animals Cell Line, Tumor Female Humans Lung Neoplasms Male MAP Kinase Signaling System Mice MicroRNAs Mutation NIH 3T3 Cells Proto-Oncogene Proteins p21(ras) ras Proteins

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