The SNAIL/miR-128 axis regulated growth, invasion, metastasis, and epithelial-to-mesenchymal transition of gastric cancer

Oncotarget. 2017 Jun 13;8(24):39280-39295. doi: 10.18632/oncotarget.16849.

Abstract

miR-128 is expressed in various tumors, but its expression and function in gastric cancer have not been defined. Thus, the goal of this study was to characterize miR-128 in gastric cancer. We found first that miR-128 is down-regulated in gastric cancer cell lines and tissues, and this dysregulation is correlated with DNA methylation and the transcription factor SNAIL. Using prediction tools, western blotting, and luciferase reporter assays, we found that Bmi-1 was the direct target of miR-128. Additionally, overexpression of miR-128 inhibited gastric cancer cell migration, invasion, and proliferation by targeting Bmi-1 in vitro and in vivo. We also documented, with receiver operating characteristic curves and Kaplan-Meier survival analysis, that miR-128 and Bmi-1 may be useful markers for diagnosing and estimating the prognosis of gastric cancer patients. As the epithelial-to-mesenchymal transition is an important mechanism associated with cancer invasion and metastasis, we inferred that miR-128 could regulate this mechanism in gastric cancer. In fact, we found that miR-128 could reverse epithelial-to-mesenchymal transition induced by Bmi-1 via the PI3K/AKT pathway. Because SNAIL also acts as a mesenchymal marker, our findings identified a novel positive feedback loop in which the transcription factor SNAIL curbs the expression of miR-128, and then down-regulated miR-128 promotes the expression of Bmi-1; finally, overexpression of Bmi-1 drives the epithelial-to-mesenchymal transition process via the PI3K/AKT pathway, and the expression of SNAIL is up-regulated.

Keywords: DNA methylation; SNAIL; gastric cancer; miR-128; transcription factor.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Movement*
  • Cell Proliferation*
  • Epithelial-Mesenchymal Transition*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Invasiveness
  • Prognosis
  • Signal Transduction
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / secondary*
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • MIRN128 microRNA, human
  • MicroRNAs
  • SNAI1 protein, human
  • Snail Family Transcription Factors