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SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5‐year survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of...

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Autores principales: Nishimura, Takao, Tamaoki, Masashi, Komatsuzaki, Rie, Oue, Naohide, Taniguchi, Hirokazu, Komatsu, Masayuki, Aoyagi, Kazuhiko, Minashi, Keiko, Chiwaki, Fumiko, Shinohara, Hisashi, Tachimori, Yuji, Yasui, Wataru, Muto, Manabu, Yoshida, Teruhiko, Sakai, Yoshiharu, Sasaki, Hiroki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329162/
https://www.ncbi.nlm.nih.gov/pubmed/27987372
http://dx.doi.org/10.1111/cas.13135
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author Nishimura, Takao
Tamaoki, Masashi
Komatsuzaki, Rie
Oue, Naohide
Taniguchi, Hirokazu
Komatsu, Masayuki
Aoyagi, Kazuhiko
Minashi, Keiko
Chiwaki, Fumiko
Shinohara, Hisashi
Tachimori, Yuji
Yasui, Wataru
Muto, Manabu
Yoshida, Teruhiko
Sakai, Yoshiharu
Sasaki, Hiroki
author_facet Nishimura, Takao
Tamaoki, Masashi
Komatsuzaki, Rie
Oue, Naohide
Taniguchi, Hirokazu
Komatsu, Masayuki
Aoyagi, Kazuhiko
Minashi, Keiko
Chiwaki, Fumiko
Shinohara, Hisashi
Tachimori, Yuji
Yasui, Wataru
Muto, Manabu
Yoshida, Teruhiko
Sakai, Yoshiharu
Sasaki, Hiroki
author_sort Nishimura, Takao
collection PubMed
description Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5‐year survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial‐mesenchymal transition (EMT) by transforming growth factor‐β (TGF‐β) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1‐transfectants. Furthermore, the SIX1‐transfectants highly expressed tumor basal cell markers such as NGFR,SOX2,ALDH1A1, and PDPN. Although mock‐transfectants had only a 20% PDPN‐high population, SIX1‐transfectants had 60–70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF‐β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN‐positive tumor basal cell population. The present results suggest that SIX1 accelerates self‐renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients.
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spelling pubmed-53291622017-03-03 SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer Nishimura, Takao Tamaoki, Masashi Komatsuzaki, Rie Oue, Naohide Taniguchi, Hirokazu Komatsu, Masayuki Aoyagi, Kazuhiko Minashi, Keiko Chiwaki, Fumiko Shinohara, Hisashi Tachimori, Yuji Yasui, Wataru Muto, Manabu Yoshida, Teruhiko Sakai, Yoshiharu Sasaki, Hiroki Cancer Sci Original Articles Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5‐year survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial‐mesenchymal transition (EMT) by transforming growth factor‐β (TGF‐β) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1‐transfectants. Furthermore, the SIX1‐transfectants highly expressed tumor basal cell markers such as NGFR,SOX2,ALDH1A1, and PDPN. Although mock‐transfectants had only a 20% PDPN‐high population, SIX1‐transfectants had 60–70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF‐β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN‐positive tumor basal cell population. The present results suggest that SIX1 accelerates self‐renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients. John Wiley and Sons Inc. 2017-02-28 2017-02 /pmc/articles/PMC5329162/ /pubmed/27987372 http://dx.doi.org/10.1111/cas.13135 Text en © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Nishimura, Takao
Tamaoki, Masashi
Komatsuzaki, Rie
Oue, Naohide
Taniguchi, Hirokazu
Komatsu, Masayuki
Aoyagi, Kazuhiko
Minashi, Keiko
Chiwaki, Fumiko
Shinohara, Hisashi
Tachimori, Yuji
Yasui, Wataru
Muto, Manabu
Yoshida, Teruhiko
Sakai, Yoshiharu
Sasaki, Hiroki
SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
title SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
title_full SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
title_fullStr SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
title_full_unstemmed SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
title_short SIX1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
title_sort six1 maintains tumor basal cells via transforming growth factor‐β pathway and associates with poor prognosis in esophageal cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329162/
https://www.ncbi.nlm.nih.gov/pubmed/27987372
http://dx.doi.org/10.1111/cas.13135
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