miR-494-3p is a novel tumor driver of lung carcinogenesis

Oncotarget. 2017 Jan 31;8(5):7231-7247. doi: 10.18632/oncotarget.13933.

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.

Keywords: NOTCH1; NSCLC; miR-494-3p; miRNA; stem cells.

MeSH terms

  • A549 Cells
  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genes, ras
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Mice, Nude
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mutation
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Prognosis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Side-Population Cells / metabolism
  • Side-Population Cells / pathology
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Burden

Substances

  • MIRN494 microRNA, human
  • MicroRNAs
  • Mirn494 microRNA, mouse
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human