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
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
View: Text | PDF
Research Article Oncology

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

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.

Authors

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

×

Figure 8

RAS/MAPK signaling is altered by miR-31 and essential for miR-31–regulated lung cell growth.

Options: View larger image (or click on image) Download as PowerPoint
RAS/MAPK signaling is altered by miR-31 and essential for miR-31–regulat...
(A) Western blots for phospho-ERK1/2 (pERK1/2) and total ERK1/2 in Beas-2B cells transfected with miR-31 mimic or RNA control at two concentrations (200 and 400 nM, referred to in the figure as 1 and 2, respectively). Densitometry values are indicated. Data are representative of 2 independent experiments. (B) Beas-2B cells transfected (performed in triplicate) with miR-31 mimic or RNA control were evaluated by intracellular phospho-flow cytometry for phospho-ERK1/2 and total ERK1/2. The MFI of pERK is relative to total ERK (*P ≤ 0.04, t tests). Data are representative of 3 independent experiments. (C) 16HBE cells were transfected with miR-31 mimic or RNA control and treated with 100 nM trametinib (Trem), selumetinib (Sel), or vehicle (DMSO) control. MTT assays were performed (performed in triplicate). Data are representative of 2 independent experiments.