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

Mick D. Edmonds, Kelli L. Boyd, Tamara Moyo, Ramkrishna Mitra, Robert Duszynski, Maria Pia Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Thomas Andl, Christine M. Eischen

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)349-364
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number1
DOIs
StatePublished - Jan 4 2016

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Edmonds, M. D., Boyd, K. L., Moyo, T., Mitra, R., Duszynski, R., Arrate, M. P., Chen, X., Zhao, Z., Blackwell, T. S., Andl, T., & Eischen, C. M. (2016). MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer. Journal of Clinical Investigation, 126(1), 349-364. https://doi.org/10.1172/JCI82720