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 1

miR-31 is overexpressed and correlates with poor survival in lung adenocarcinoma.

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miR-31 is overexpressed and correlates with poor survival in lung adenoc...
(A) qRT-PCR analysis (performed in triplicate) of miR-31 expression in human lung epithelial and adenocarcinoma cells lines. ΔCt values graphed are relative to the endogenous control RNU6B small RNA with SEM. *P ≤ 0.0012, t test. Data are representative of 3 independent experiments. (B and C) qRT-PCR analysis of miR-31 expression in normal human lung tissue and (B) all human lung adenocarcinoma samples or (C) samples separated by stage of disease. miR-31 expression relative to RNU6B; mean values are indicated by solid bars, and values are shown as mean ± SEM. *P = 0.004; #P = 0.0009; **P = 0.0017; ##P = 0.0001, t test. The number of samples is shown. (D) miR-31 expression in normal lung and lung adenocarcinomas from TCGA miR expression profiles displayed as log2-transformed values normalized to reads per million. *P = 4.99 × 10–14, t test. (E) Data from D separated by stage. *P = 4.8 × 10–13; #P = 5.3 × 10–10; §P = 3.4 × 10–10; **P = 9.3 × 10–06, t tests. The number of samples is shown. (F and G) Kaplan-Meier analysis with (F) median (158 samples for each) and (G) lowest (n = 79) and highest (n = 79) quartiles of miR-31 expression for lung adenocarcinoma from TCGA expression data. P values were determined by log-rank test.