MiR-203a functions as a tumor suppressor in bladder cancer by targeting SIX4

Neoplasma. 2019 Mar 5;66(2):211-221. doi: 10.4149/neo_2018_180512N312. Epub 2018 Sep 29.


Increasing evidence indicates that microRNAs (miRNAs) have essential roles in various biological processes, including proliferation, migration, invasion, cell cycle progression and apoptosis. It is considered that miRNA de-regulation contributes to tumor progression and metastasis in various cancers, and MiR-203a has been identified as a tumor suppressor in cancers, such as glioma, gastric cancer and hepatocellular carcinoma. Herein, we established that miR-203a expression is significantly lower in bladder cancer tissues than in adjacent normal tissues, and that low miR-203a expression is associated with poor patient outcome. The over-expression of miR-203a inhibited bladder cancer cell proliferation, invasion, migration and EMT in vitro, and its up-regulation led to bladder cancer cell cycle arrest and apoptosis. This over-expression also inhibited the PI3K/Akt signaling pathway. Bioinformatics prediction software and luciferase reporter assay then confirmed that SIX4 is a direct target of miR-203a. We established negative correlation between SIX4 expression and miR-203a expression in bladder cancer tissues, and SIX4 silencing caused effects similar to miR-203a up-regulation Furthermore, SIX4 over-expression diminished the effects of miR-203a on bladder cancer cells in vitro. In summary, our study determined that miR-203a down-regulation is closely related to tumorigenesis in bladder cancer; thus suggesting that miR-203a is a potential prognostic marker and a potential target in bladder cancer treatment.

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics*
  • Humans
  • MicroRNAs / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Trans-Activators / genetics*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology


  • Homeodomain Proteins
  • MIRN203 microRNA, human
  • MicroRNAs
  • SIX4 protein, human
  • Trans-Activators
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt