Abstract LB-168: MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer deaths and yet the genes that drive this malignancy are not entirely known. MicroRNA (miRNA) are important regulators of gene expression and aberrant miRNA expression has been linked to lung oncogenesis; however, little known about their contribution in tumor initiation. We’ve determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. miR-31 promotes lung cell proliferation and adenocarcinoma growth in vivo. We also 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. We identified 6 negative regulators of RAS/MAPK signaling (RASA1, SPRED1, SPRED2, SPRY1, SPRY3, SPRY4) as direct targets of miR-31. Analysis of human lung adenocarcinoma revealed that high miR-31 expression correlated to decreased target mRNA expression. miR-31 overexpression in lung cells results in increased RAS signaling and pharmacologic inhibition of MEK ablates miR-31 induced lung cell proliferation. Induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. Our study demonstrates for the first time that a miRNA can drive an epithelial cancer. Specifically we identified miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and demonstrate that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling. Citation Format: Mick D. Edmonds, Kelli L. Boyd, Tamara K. Moyo, Ramkrishna Mitra, Robert J. Duszynski, Maria P. Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Christine M. Eischen. MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-168.