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Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the regulation of gene expression. Previous reports showed an over-expression of miRNA-21 (miR-21) in various cancer cells, and its up-regulation is closely related to cancer initiation, proliferation and metastasis. In this work, we...

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Detalles Bibliográficos
Autores principales: Larcher, Leon M., Wang, Tao, Veedu, Rakesh N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651226/
https://www.ncbi.nlm.nih.gov/pubmed/31284665
http://dx.doi.org/10.3390/molecules24132489
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author Larcher, Leon M.
Wang, Tao
Veedu, Rakesh N.
author_facet Larcher, Leon M.
Wang, Tao
Veedu, Rakesh N.
author_sort Larcher, Leon M.
collection PubMed
description MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the regulation of gene expression. Previous reports showed an over-expression of miRNA-21 (miR-21) in various cancer cells, and its up-regulation is closely related to cancer initiation, proliferation and metastasis. In this work, we envisioned the development of novel antimiRzymes (anti-miRNA-DNAzyme) that are capable of selectively targeting and cleaving miR-21 and inhibit its expression in cancer cells using the DNAzyme technique. For this purpose, we have designed different antimiRzyme candidates by systematically targeting different regions of miR-21. Our results demonstrated that RNV541, a potential arm-loop-arm type antimiRzyme, was very efficient (90%) to suppress miR-21 expression in U87MG malignant glioblastoma cell line at 200 nM concentration. In addition, RNV541 also inhibited miR-21 expression (50%) in MDA-MB-231 breast cancer cell line. For targeted delivery, we conjugated RNV541 with a transferrin receptor (TfR) targeting aptamer for TfR-mediated cancer cell delivery. As expected, the developed chimeric structure efficiently delivered the antimiRzyme RNV541 into TfR positive glioblastoma cells. TfR aptamer-RNV541 chimeric construct showed 52% inhibition of miR-21 expression in U87MG glioblastoma cells at 2000 nM concentration, without using any transfection reagents, making it a highly desirable strategy to tackle miR-21 over-expressed malignant cancers. Although these are in vitro based observations, based on our results, we firmly believe that our findings could be beneficial towards the development of targeted cancer therapeutics where conventional therapies face several challenges.
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spelling pubmed-66512262019-08-07 Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells Larcher, Leon M. Wang, Tao Veedu, Rakesh N. Molecules Article MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the regulation of gene expression. Previous reports showed an over-expression of miRNA-21 (miR-21) in various cancer cells, and its up-regulation is closely related to cancer initiation, proliferation and metastasis. In this work, we envisioned the development of novel antimiRzymes (anti-miRNA-DNAzyme) that are capable of selectively targeting and cleaving miR-21 and inhibit its expression in cancer cells using the DNAzyme technique. For this purpose, we have designed different antimiRzyme candidates by systematically targeting different regions of miR-21. Our results demonstrated that RNV541, a potential arm-loop-arm type antimiRzyme, was very efficient (90%) to suppress miR-21 expression in U87MG malignant glioblastoma cell line at 200 nM concentration. In addition, RNV541 also inhibited miR-21 expression (50%) in MDA-MB-231 breast cancer cell line. For targeted delivery, we conjugated RNV541 with a transferrin receptor (TfR) targeting aptamer for TfR-mediated cancer cell delivery. As expected, the developed chimeric structure efficiently delivered the antimiRzyme RNV541 into TfR positive glioblastoma cells. TfR aptamer-RNV541 chimeric construct showed 52% inhibition of miR-21 expression in U87MG glioblastoma cells at 2000 nM concentration, without using any transfection reagents, making it a highly desirable strategy to tackle miR-21 over-expressed malignant cancers. Although these are in vitro based observations, based on our results, we firmly believe that our findings could be beneficial towards the development of targeted cancer therapeutics where conventional therapies face several challenges. MDPI 2019-07-07 /pmc/articles/PMC6651226/ /pubmed/31284665 http://dx.doi.org/10.3390/molecules24132489 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Larcher, Leon M.
Wang, Tao
Veedu, Rakesh N.
Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells
title Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells
title_full Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells
title_fullStr Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells
title_full_unstemmed Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells
title_short Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells
title_sort development of novel antimirzymes for targeted inhibition of mir-21 expression in solid cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651226/
https://www.ncbi.nlm.nih.gov/pubmed/31284665
http://dx.doi.org/10.3390/molecules24132489
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