Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer

Sci Rep. 2017 Jan 10;7:40487. doi: 10.1038/srep40487.

Abstract

The role of osteoclastic miRNAs in regulating osteolytic bone metastasis (OBM) of breast cancer is still underexplored. Here, we examined the expression profiles of osteoclastogenic miRNAs in human bone specimens and identified that miR-214-3p was significantly upregulated in breast cancer patients with OBM. Consistently, we found increased miR-214-3p within osteoclasts, which was associated with the elevated bone resorption, during the development of OBM in human breast cancer xenografted nude mice (BCX). Furthermore, genetic ablation of osteoclastic miR-214-3p in nude mice prevent the development of OBM. Conditioned medium from MDA-MB-231 cells dramatically stimulated miR-214-3p expression to promote osteoclast differentiation. Mechanistically, a series of in vitro study showed that miR-214-3p directly targeted Traf3 to promote osteoclast activity and bone-resorbing activity. In addition, osteoclast-specific miR-214-3p knock-in mice showed remarkably increased bone resorption when compared to the littermate controls, which was attenuated after osteoclast-targeted treatment with Traf3 3'UTR-containing plasmid. In BCX nude mice, osteoclast-targeted antagomir-214-3p delivery could recover the TRAF3 protein expression and attenuate the development of OBM, respectively. Collectively, inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer patients with OBM. Meanwhile, the intraosseous TRAF3 could be a promising biomarker for evaluation of the treatment response of antagomir-214-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary*
  • Bone Resorption / pathology
  • Breast Neoplasms / pathology*
  • Cell Differentiation
  • Cell Line, Tumor
  • Female
  • Liposomes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Osteolysis / metabolism
  • Osteolysis / pathology*
  • RAW 264.7 Cells
  • TNF Receptor-Associated Factor 3 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Liposomes
  • MicroRNAs
  • Mirn214 microRNA, mouse
  • TNF Receptor-Associated Factor 3