Abstract
Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically, ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population, enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR-494-3p as a key factor in lung cancer onset and progression and possible therapeutic target.
Original language | English |
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Pages (from-to) | 7231-7247 |
Number of pages | 17 |
Journal | Oncotarget |
Volume | 8 |
Issue number | 5 |
DOIs | |
Publication status | Published - Jan 31 2017 |
Keywords
- A549 Cells
- Animals
- Cell Movement
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Disease Models, Animal
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Genes, ras
- Humans
- Kaplan-Meier Estimate
- Lung Neoplasms/genetics
- Male
- Mice, Nude
- Mice, Transgenic
- MicroRNAs/genetics
- Mutation
- Neoplasm Invasiveness
- Neoplastic Stem Cells/metabolism
- PTEN Phosphohydrolase/genetics
- Phosphatidylinositol 3-Kinase/metabolism
- Prognosis
- Proto-Oncogene Proteins c-akt/metabolism
- Receptor, Notch1/genetics
- Side-Population Cells/metabolism
- Signal Transduction
- Time Factors
- Transfection
- Tumor Burden