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

doi:10.1016/j.omtn.2021.01.016

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

Mol Ther Nucleic Acids. 2021 Jan 20:23:930-943. doi: 10.1016/j.omtn.2021.01.016. eCollection 2021 Mar 5.

Authors

Aysegul Gorur^{1

2}, Recep Bayraktar¹, Cristina Ivan^{1

3}, Hamada Ahmed Mokhlis^{1

4}, Emine Bayraktar¹, Nermin Kahraman¹, Didem Karakas¹, Selda Karamil¹, Nashwa N Kabil¹, Pinar Kanlikilicer¹, Burcu Aslan¹, Lulufer Tamer², Zhihui Wang⁵, Vittorio Cristini⁵, Gabriel Lopez-Berestein^{1

3}, George Calin^{1

3}, Bulent Ozpolat^{1

3}

Affiliations

¹ Department of Experimental Therapeutics, Unit 1950, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
² Department of Biochemistry, School of Medicine, Mersin University, Mersin, Turkey.
³ Center for RNA Interference and Non-Coding RNAs, Unit 2080, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁴ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁵ Mathematics in Medicine, Houston Methodist Research Institute, 6565 Fannin Street, Houston, TX 77030, USA.

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.

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

Abstract

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