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

Molecular Therapy: Nucleic Acids

Emine Bayraktar¹  Recep Bayraktar²  Didem Karakas³  Gabriel Lopez-Berestein⁴  Nermin Kahraman⁵  Lulufer Tamer⁵  Nashwa N. Kabil⁵  Burcu Aslan⁵  Aysegul Gorur⁵  Pinar Kanlikilicer⁵  Hamada Ahmed Mokhlis⁵  Cristina Ivan⁵  Vittorio Cristini⁵  Zhihui Wang⁵  Selda Karamil⁵  George Calin⁶  Bulent Ozpolat⁶ 

[1] 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;Department of Biochemistry, School of Medicine, Mersin University, Mersin, Turkey;Department of Pharmacology and Toxicology, Faculty of Pharmacy, The University of Al-Azhar, Cairo, Egypt;Department of Biochemistry, School of Medicine, Mersin University, Mersin, Turkey;Department of Experimental Therapeutics, Unit 1950, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA;Mathematics in Medicine, Houston Methodist Research Institute, 6565 Fannin Street, Houston, TX 77030, USA;

关键词: triple-negative breast cancer;    breast cancer;    miR-22;    Src;    eEF2K;    EF2K;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown