ncRNA therapy with miRNA-22-3p suppresses the growth of triple-negative breast cancer
| Autor: | Pinar Kanlikilicer, Bulent Ozpolat, Emine Bayraktar, Selda Karamil, Burcu Aslan, Gabriel Lopez-Berestein, Cristina Ivan, Nashwa N. Kabil, Vittorio Cristini, Aysegul Gorur, Hamada Ahmed Mokhlis, Didem Karakas, Recep Bayraktar, Lülüfer Tamer, George A. Calin, Nermin Kahraman, Zhihui Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
liposomes tumor suppressor miR-22 Biology PI3K 03 medical and health sciences gene silencing 0302 clinical medicine Breast cancer breast cancer Drug Discovery microRNA medicine Gene silencing Protein kinase B PI3K/AKT/mTOR pathway Triple-negative breast cancer Regulation of gene expression therapy Akt lcsh:RM1-950 eEF2K medicine.disease Non-coding RNA EF2K 030104 developmental biology lcsh:Therapeutics. Pharmacology 030220 oncology & carcinogenesis Cancer research triple-negative breast cancer Molecular Medicine Original Article nanoparticles gene regulation Src |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 23, Iss, Pp 930-943 (2021) |
| ISSN: | 2162-2531 |
| Popis: | 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. Graphical Abstract Our study demonstrates that microRNA-22-3p (miR-22-3p) acts as a tumor suppressor in which its expression is markedly reduced in TNBC tumors. Restoration of its expression by miR-22-3p nanotherapy suppress tumor growth and progression by directly inhibiting of eEF2K-PI3K/AKT and Src signaling. miR-22-3p-based RNA therapy may be novel treatment for TNBC. |
| Databáze: | OpenAIRE |
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