MicroRNA-374a Inhibits Aggressive Tumor Biological Behavior in Bladder Carcinoma by Suppressing Wnt/β-Catenin Signaling

Cell Physiol Biochem. 2018;48(2):815-826. doi: 10.1159/000491911. Epub 2018 Jul 20.

Abstract

Background/aims: microRNA (miR)-374a plays a crucial role in cancer progression by promoting the metastasis and proliferation of various types of malignant tumors. Because its role in bladder cancer is unknown, we investigated whether miR-374a affects the progression of bladder cancer and studied the underlying mechanism.

Methods: The Cancer Genome Atlas was used to analyze the clinical relevance of miR-374a. Quantitative PCR, western blotting, and luciferase and immunofluorescence assays were used to detect the expression patterns, downstream targets, and function of miR-374a in bladder cancer cells. Apoptosis was evaluated by flow cytometry after cisplatin treatment.

Results: Via in silico analysis, low levels of miR-374a were associated with poor prognosis in bladder cancer patients with distant metastasis. WNT5A was a direct target of miR-374a in two bladder cancer cell lines. miR-374a mimic abrogated the metastatic potential and invasiveness of bladder cancer cells via WNT5A downregulation in both T24 and TCCSUP human bladder cancer cells; the opposite was observed with miR-374a inhibitor. In addition, miR-374a treatment reduced the phosphorylation and nuclear translocation of β-catenin. Cisplatin treatment significantly increased the apoptosis rate. Expression levels of cancer stemness-related proteins were reduced in miR-374a mimic-pretreated cells.

Conclusion: Lower expression of miR-374a is associated with poor prognosis and miR-374a improves tumor biological behavior in bladder cancer cells, suggesting that miR-374a might be a novel small-molecule therapeutic target.

Keywords: Bladder cancer; Metastasis; Mir-374a; WNT5A; Wnt/β-catenin.

MeSH terms

  • 3' Untranslated Regions
  • Antagomirs / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Base Sequence
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Databases, Genetic
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Phosphorylation
  • Sequence Alignment
  • Survival Rate
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology*
  • Wnt Signaling Pathway
  • Wnt-5a Protein / chemistry
  • Wnt-5a Protein / genetics
  • Wnt-5a Protein / metabolism*
  • beta Catenin / metabolism

Substances

  • 3' Untranslated Regions
  • Antagomirs
  • Antineoplastic Agents
  • MIRN374 microRNA 374, human
  • MicroRNAs
  • WNT5A protein, human
  • Wnt-5a Protein
  • beta Catenin
  • Glycogen Synthase Kinase 3 beta
  • Cisplatin