ncRNA therapy with miRNA-22-3p suppresses the growth of triple-negative breast cancer

Aysegul Gorur, Recep Bayraktar, Cristina Ivan, Hamada Ahmed Mokhlis, Emine Bayraktar, Nermin Kahraman, Didem Karakas, Selda Karamil, Nashwa N. Kabil, Pinar Kanlikilicer, Burcu Aslan, Lulufer Tamer, Zhihui Wang, Vittorio Cristini, Gabriel Lopez-Berestein, George Calin, Bulent Ozpolat

Research output: Contribution to journalArticle

Abstract

Deregulation of noncoding RNAs, including microRNAs (miRs), is implicated in the pathogenesis of many human cancers, including breast cancer. Through extensive analysis of The Cancer Genome Atlas, we found that expression of miR-22-3p is markedly lower in triple-negative breast cancer (TNBC) than in normal breast tissue. The restoration of miR-22-3p expression led to significant inhibition of TNBC cell proliferation, colony formation, migration, and invasion. We demonstrated that miR-22-3p reduces eukaryotic elongation factor 2 kinase (eEF2K) expression by directly binding to the 3′ untranslated region of eEF2K mRNA. Inhibition of EF2K expression recapitulated the effects of miR-22-3p on TNBC cell proliferation, motility, invasion, and suppression of phosphatidylinositol 3-kinase/Akt and Src signaling. Systemic administration of miR-22-3p in single-lipid nanoparticles significantly suppressed tumor growth in orthotopic MDA-MB-231 and MDA-MB-436 TNBC models. Evaluation of the tumor response, following miR-22-3p therapy in these models using a novel mathematical model factoring in various in vivo parameters, demonstrated that the therapy is highly effective against TNBC. These findings suggest that miR-22-3p functions as a tumor suppressor by targeting clinically significant oncogenic pathways and that miR-22-3p loss contributes to TNBC growth and progression. The restoration of miR-22-3p expression is a potential novel noncoding RNA-based therapy for TNBC.

Original languageEnglish (US)
Pages (from-to)930-943
Number of pages14
JournalMolecular Therapy - Nucleic Acids
Volume23
DOIs
StatePublished - Mar 5 2021

Keywords

  • Akt
  • breast cancer
  • eEF2K
  • EF2K
  • gene regulation
  • gene silencing
  • liposomes
  • miR-22
  • nanoparticles
  • PI3K
  • Src
  • therapy
  • triple-negative breast cancer
  • tumor suppressor

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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