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Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy

Dysregulation of miRNA expression has been implicated in cancer. Numerous strategies have been explored to modulate miR but sub-optimal delivery and inability to concurrently target multiple pathways involved in tumor progression have limited their efficacy. In this study, we explored the potential...

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Autores principales: Bhere, Deepak, Arghiani, Nahid, Lechtich, Esther Revai, Yao, Yizheng, Alsaab, Sarah, Bei, Fengfeng, Matin, Maryam M., Shah, Khalid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000780/
https://www.ncbi.nlm.nih.gov/pubmed/32019988
http://dx.doi.org/10.1038/s41598-020-58072-w
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author Bhere, Deepak
Arghiani, Nahid
Lechtich, Esther Revai
Yao, Yizheng
Alsaab, Sarah
Bei, Fengfeng
Matin, Maryam M.
Shah, Khalid
author_facet Bhere, Deepak
Arghiani, Nahid
Lechtich, Esther Revai
Yao, Yizheng
Alsaab, Sarah
Bei, Fengfeng
Matin, Maryam M.
Shah, Khalid
author_sort Bhere, Deepak
collection PubMed
description Dysregulation of miRNA expression has been implicated in cancer. Numerous strategies have been explored to modulate miR but sub-optimal delivery and inability to concurrently target multiple pathways involved in tumor progression have limited their efficacy. In this study, we explored the potential co-modulation of upregulated miR-21 and downregulated miR-7 to enhance therapeutic outcomes in heterogenic tumor types. We first engineered lentiviral (LV) and adeno-associated viral (AAV) vectors that preferentially express anti-sense miR against miR-21(miRzip-21) and show that modulating miR-21 via miRzip extensively targets tumor cell proliferation, migration and invasion in vitro in a broad spectrum of cancer types and has therapeutic efficacy in vivo. Next, we show a significantly increased expression of caspase-mediated apoptosis by simultaneously downregulating miR-21 and upregulating miR-7 in different tumor cells. In vivo co-treatment with AAV-miRzip-21 and AAV-miR-7 in mice bearing malignant brain tumors resulted in significantly decreased tumor burden with a corresponding increase in survival. To our knowledge, this is the first study that demonstrates the therapeutic efficacy of simultaneously upregulating miR-7 and downregulating miR-21 and establishes a roadmap towards clinical translation of modulating miRs for various cancer types.
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spelling pubmed-70007802020-02-11 Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy Bhere, Deepak Arghiani, Nahid Lechtich, Esther Revai Yao, Yizheng Alsaab, Sarah Bei, Fengfeng Matin, Maryam M. Shah, Khalid Sci Rep Article Dysregulation of miRNA expression has been implicated in cancer. Numerous strategies have been explored to modulate miR but sub-optimal delivery and inability to concurrently target multiple pathways involved in tumor progression have limited their efficacy. In this study, we explored the potential co-modulation of upregulated miR-21 and downregulated miR-7 to enhance therapeutic outcomes in heterogenic tumor types. We first engineered lentiviral (LV) and adeno-associated viral (AAV) vectors that preferentially express anti-sense miR against miR-21(miRzip-21) and show that modulating miR-21 via miRzip extensively targets tumor cell proliferation, migration and invasion in vitro in a broad spectrum of cancer types and has therapeutic efficacy in vivo. Next, we show a significantly increased expression of caspase-mediated apoptosis by simultaneously downregulating miR-21 and upregulating miR-7 in different tumor cells. In vivo co-treatment with AAV-miRzip-21 and AAV-miR-7 in mice bearing malignant brain tumors resulted in significantly decreased tumor burden with a corresponding increase in survival. To our knowledge, this is the first study that demonstrates the therapeutic efficacy of simultaneously upregulating miR-7 and downregulating miR-21 and establishes a roadmap towards clinical translation of modulating miRs for various cancer types. Nature Publishing Group UK 2020-02-04 /pmc/articles/PMC7000780/ /pubmed/32019988 http://dx.doi.org/10.1038/s41598-020-58072-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bhere, Deepak
Arghiani, Nahid
Lechtich, Esther Revai
Yao, Yizheng
Alsaab, Sarah
Bei, Fengfeng
Matin, Maryam M.
Shah, Khalid
Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy
title Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy
title_full Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy
title_fullStr Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy
title_full_unstemmed Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy
title_short Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy
title_sort simultaneous downregulation of mir-21 and upregulation of mir-7 has anti-tumor efficacy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000780/
https://www.ncbi.nlm.nih.gov/pubmed/32019988
http://dx.doi.org/10.1038/s41598-020-58072-w
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