Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B

Nat Commun. 2015 Jan 8;6:5917. doi: 10.1038/ncomms6917.

Abstract

Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Here we reveal a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late-state ovarian tumours, as compared with normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chromatin Immunoprecipitation
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / genetics
  • Glucocorticoids / metabolism
  • Glucocorticoids / pharmacology*
  • Heterografts / metabolism*
  • Humans
  • In Situ Hybridization
  • Luciferases
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness / prevention & control
  • Neoplasm Metastasis / prevention & control*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Real-Time Polymerase Chain Reaction
  • rap GTP-Binding Proteins / metabolism*

Substances

  • Glucocorticoids
  • MIRN708 microRNA, human
  • MicroRNAs
  • Luciferases
  • RAP1B protein, human
  • rap GTP-Binding Proteins