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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...

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Autores principales: Yokota, Etsuko, Yamatsuji, Tomoki, Takaoka, Munenori, Haisa, Minoru, Takigawa, Nagio, Miyake, Noriko, Ikeda, Tomoko, Mori, Tomoaki, Ohno, Serika, Sera, Takashi, Fukazawa, Takuya, Naomoto, Yoshio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
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.
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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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