MicroRNA-31 initiates lung turnorigenesis and promotes mutant KRAS-driven lung cancer
MicroRNA-31 initiates lung turnorigenesis and promotes mutant KRAS-driven lung cancer
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DOI：
10.1172/jci82720
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发表时间：
2016-01-01
影响因子：
15.9
通讯作者：
Eischen, Christine M.
中科院分区：
文献类型：
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作者：
Edmonds, Mick D.;Boyd, Kelli L.;Eischen, Christine M.
MicroRNA(MiR)是基因表达的重要调节因子，miR的异常表达与肿瘤的发生有关，但对其在肺肿瘤发生中的作用却知之甚少。在这里，我们确定miR-31在人类肺腺癌中过度表达，这种过度表达与患者生存率下降独立相关。我们开发了一种转基因小鼠模型，允许miR-31在肺中特异性表达，以测试miR-31在肺中的致癌潜力。使用这个模型，我们观察到miR-31诱导导致肺组织增生，随后是腺瘤形成和腺癌的发展。此外，在小鼠体内诱导miR-31的表达与突变的KRAS协同促进了肺肿瘤的形成。我们确定了miR-31调节肺上皮细胞生长，并确定了6个RAS/MAPK信号负调控因子作为miR-31的直接靶点。我们的研究区分了miR-31是促进突变的KRAS介导的肿瘤发生的肺肿瘤发生的驱动因素，并揭示了miR-31直接靶向和减少RAS/MAPK信号的负调控因子的表达。
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.