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Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma
SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a z...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732711/ https://www.ncbi.nlm.nih.gov/pubmed/29262545 http://dx.doi.org/10.18632/oncotarget.21523 |
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author | Yokota, Etsuko Yamatsuji, Tomoki Takaoka, Munenori Haisa, Minoru Takigawa, Nagio Miyake, Noriko Ikeda, Tomoko Mori, Tomoaki Ohno, Serika Sera, Takashi Fukazawa, Takuya Naomoto, Yoshio |
author_facet | Yokota, Etsuko Yamatsuji, Tomoki Takaoka, Munenori Haisa, Minoru Takigawa, Nagio Miyake, Noriko Ikeda, Tomoko Mori, Tomoaki Ohno, Serika Sera, Takashi Fukazawa, Takuya Naomoto, Yoshio |
author_sort | Yokota, Etsuko |
collection | PubMed |
description | SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC. |
format | Online Article Text |
id | pubmed-5732711 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57327112017-12-19 Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma Yokota, Etsuko Yamatsuji, Tomoki Takaoka, Munenori Haisa, Minoru Takigawa, Nagio Miyake, Noriko Ikeda, Tomoko Mori, Tomoaki Ohno, Serika Sera, Takashi Fukazawa, Takuya Naomoto, Yoshio Oncotarget Research Paper SOX2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad-ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC. Impact Journals LLC 2017-10-05 /pmc/articles/PMC5732711/ /pubmed/29262545 http://dx.doi.org/10.18632/oncotarget.21523 Text en Copyright: © 2017 Yokota et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yokota, Etsuko Yamatsuji, Tomoki Takaoka, Munenori Haisa, Minoru Takigawa, Nagio Miyake, Noriko Ikeda, Tomoko Mori, Tomoaki Ohno, Serika Sera, Takashi Fukazawa, Takuya Naomoto, Yoshio Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
title | Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
title_full | Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
title_fullStr | Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
title_full_unstemmed | Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
title_short | Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
title_sort | targeted silencing of sox2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732711/ https://www.ncbi.nlm.nih.gov/pubmed/29262545 http://dx.doi.org/10.18632/oncotarget.21523 |
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