Exosomes Mediated Transfer of Circ_UBE2D2 Enhances the Resistance of Breast Cancer to Tamoxifen by Binding to MiR-200a-3p

Med Sci Monit. 2020 Aug 5;26:e922253. doi: 10.12659/MSM.922253.

Abstract

BACKGROUND Circular RNA UBE2D2 (circ_UBE2D2) has been found to be involved in the progression of breast cancer. Exosomes are critical mediators of intercellular communication, however, the function of exosomal circ_UBE2D2 in breast cancer remains vague. MATERIAL AND METHODS Cell viability was measured by Cell Counting Kit-8 assay. Western blot was used to detect the levels of estrogen receptor alpha (ERalpha), E-cadherin, vimentin, CD9, and CD63. Migrated and invaded cells were examined using Transwell assay. Circ_UBE2D2 and microRNA (miR)-200a-3p levels were detected using quantitative real-time polymerase chain reaction. Exosomes were isolated by ultracentrifugation method. The interaction between circ_UBE2D2 and miR-200a-3p was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Murine xenograft model was established to conduct in vivo experiments. RESULTS We found that circ_UBE2D2 was upregulated in breast cancer tamoxifen-resistant tissues and cell lines, and circ_UBE2D2 deletion mitigated tamoxifen resistance in breast cancer cells. Circ_UBE2D2 was also significantly loaded in exosomes isolated from resistant cells and could be transferred to parental cells. MiR-200a-3p was a target of circ_UBE2D2, and we demonstrated that exosomes mediated transfer of circ_UBE2D2 interacted with miR-200a-3p to enhance tamoxifen resistance of breast cancer cells by regulating cell viability, metastasis, and the level of ERalpha in vivo and in vitro. CONCLUSIONS Exosomes mediated transfer of circ_UBE2D2 reinforced tamoxifen resistance in breast cancer by binding to miR-200a-3p, providing new insights into the boost of the effectiveness of tamoxifen on breast cancer patients.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Estrogen Antagonists / pharmacology*
  • Estrogen Receptor alpha / metabolism
  • Exosomes / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA Interference
  • RNA, Circular / genetics
  • RNA, Circular / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tamoxifen / pharmacology*
  • Transfection
  • Tumor Burden / drug effects
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • ESR1 protein, human
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • MIRN200 microRNA, human
  • MicroRNAs
  • RNA, Circular
  • Tamoxifen
  • UBE2D2 protein, human
  • Ubiquitin-Conjugating Enzymes