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A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs
Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3′ UTR sensor vectors can be used as a pathway-based meth...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335585/ https://www.ncbi.nlm.nih.gov/pubmed/30629937 http://dx.doi.org/10.1016/j.stemcr.2018.12.002 |
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author | Belur Nagaraj, Anil Joseph, Peronne Ponting, Erin Fedorov, Yuriy Singh, Salendra Cole, Alex Lee, Woncheol Yoon, Euisik Baccarini, Alessia Scacheri, Peter Buckanovich, Ronald Adams, Drew J. Drapkin, Ronny Brown, Brian D. DiFeo, Analisa |
author_facet | Belur Nagaraj, Anil Joseph, Peronne Ponting, Erin Fedorov, Yuriy Singh, Salendra Cole, Alex Lee, Woncheol Yoon, Euisik Baccarini, Alessia Scacheri, Peter Buckanovich, Ronald Adams, Drew J. Drapkin, Ronny Brown, Brian D. DiFeo, Analisa |
author_sort | Belur Nagaraj, Anil |
collection | PubMed |
description | Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3′ UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181a(high) subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs. |
format | Online Article Text |
id | pubmed-6335585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-63355852019-01-22 A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs Belur Nagaraj, Anil Joseph, Peronne Ponting, Erin Fedorov, Yuriy Singh, Salendra Cole, Alex Lee, Woncheol Yoon, Euisik Baccarini, Alessia Scacheri, Peter Buckanovich, Ronald Adams, Drew J. Drapkin, Ronny Brown, Brian D. DiFeo, Analisa Stem Cell Reports Article Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3′ UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181a(high) subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs. Elsevier 2019-01-08 /pmc/articles/PMC6335585/ /pubmed/30629937 http://dx.doi.org/10.1016/j.stemcr.2018.12.002 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Belur Nagaraj, Anil Joseph, Peronne Ponting, Erin Fedorov, Yuriy Singh, Salendra Cole, Alex Lee, Woncheol Yoon, Euisik Baccarini, Alessia Scacheri, Peter Buckanovich, Ronald Adams, Drew J. Drapkin, Ronny Brown, Brian D. DiFeo, Analisa A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs |
title | A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs |
title_full | A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs |
title_fullStr | A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs |
title_full_unstemmed | A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs |
title_short | A miRNA-Mediated Approach to Dissect the Complexity of Tumor-Initiating Cell Function and Identify miRNA-Targeting Drugs |
title_sort | mirna-mediated approach to dissect the complexity of tumor-initiating cell function and identify mirna-targeting drugs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335585/ https://www.ncbi.nlm.nih.gov/pubmed/30629937 http://dx.doi.org/10.1016/j.stemcr.2018.12.002 |
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