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
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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

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Figure 4

miR-31 initiates benign and malignant lung tumor formation in vivo.

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miR-31 initiates benign and malignant lung tumor formation in vivo. Coho...
Cohorts of miR-31/CCSP and littermate CCSP control mice were given dox in their drinking water for (A and B) 2 months, (C) 4 months, (D and E) 12 months, or (F–J) 18 months. (A, C, and G–I) Representative photographs of H&E-stained lung sections from miR-31/CCSP mice (original magnification: ×2 [H, left]; ×4 [G]; ×10 [A and C, left, and H, right]; ×20 [I]; ×40 [A and C, right]). Larger histology pictures are shown in Supplemental Figure 5. (B) Ki67 IHC was performed on lung sections (*P = 0.00124, t test). The number of mice evaluated is denoted by n values. (D and F) Representative photographs of (D) Bouin’s fixed lungs and (F) gross lungs, with arrows pointing to tumors. (E) Lung surface tumor nodules were counted on Bouin’s fixed lungs (*P > 0.03, t test). The number of mice evaluated is denoted by n values. (I) Representative photograph of an H&E-stained section of lung adenocarcinoma showing invasion into a blood vessel. (J) Tumor burden was determined by comparing the area of tumor to that of normal lung from H&E-stained lung sections (*P = 0.0145, t test). The number of mice evaluated is denoted by n values. (K) The mean tumor diameter for lung tumors in miR-31/CCSP mice given dox for the indicated intervals was determined from H&E-stained sections.