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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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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. |
format | Online Article Text |
id | pubmed-5329162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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