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Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers

BACKGROUND: Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial–mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might acceler...

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Autores principales: Kohnoh, Takashi, Hashimoto, Naozumi, Ando, Akira, Sakamoto, Koji, Miyazaki, Shinichi, Aoyama, Daisuke, Kusunose, Masaaki, Kimura, Motohiro, Omote, Norihito, Imaizumi, Kazuyoshi, Kawabe, Tsutomu, Hasegawa, Yoshinori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836157/
https://www.ncbi.nlm.nih.gov/pubmed/27095949
http://dx.doi.org/10.1186/s12935-016-0308-3
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author Kohnoh, Takashi
Hashimoto, Naozumi
Ando, Akira
Sakamoto, Koji
Miyazaki, Shinichi
Aoyama, Daisuke
Kusunose, Masaaki
Kimura, Motohiro
Omote, Norihito
Imaizumi, Kazuyoshi
Kawabe, Tsutomu
Hasegawa, Yoshinori
author_facet Kohnoh, Takashi
Hashimoto, Naozumi
Ando, Akira
Sakamoto, Koji
Miyazaki, Shinichi
Aoyama, Daisuke
Kusunose, Masaaki
Kimura, Motohiro
Omote, Norihito
Imaizumi, Kazuyoshi
Kawabe, Tsutomu
Hasegawa, Yoshinori
author_sort Kohnoh, Takashi
collection PubMed
description BACKGROUND: Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial–mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. METHODS: Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. RESULTS: Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus. CONCLUSION: Our study strengthens the therapeutic possibility that compensatory induction of unphosphorylated PTEN may inhibit the acquisition of EMT phenotypes in lung cancer cells under persistent hypoxia.
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spelling pubmed-48361572016-04-20 Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers Kohnoh, Takashi Hashimoto, Naozumi Ando, Akira Sakamoto, Koji Miyazaki, Shinichi Aoyama, Daisuke Kusunose, Masaaki Kimura, Motohiro Omote, Norihito Imaizumi, Kazuyoshi Kawabe, Tsutomu Hasegawa, Yoshinori Cancer Cell Int Primary Research BACKGROUND: Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial–mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. METHODS: Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. RESULTS: Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus. CONCLUSION: Our study strengthens the therapeutic possibility that compensatory induction of unphosphorylated PTEN may inhibit the acquisition of EMT phenotypes in lung cancer cells under persistent hypoxia. BioMed Central 2016-04-18 /pmc/articles/PMC4836157/ /pubmed/27095949 http://dx.doi.org/10.1186/s12935-016-0308-3 Text en © Kohnoh et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Primary Research
Kohnoh, Takashi
Hashimoto, Naozumi
Ando, Akira
Sakamoto, Koji
Miyazaki, Shinichi
Aoyama, Daisuke
Kusunose, Masaaki
Kimura, Motohiro
Omote, Norihito
Imaizumi, Kazuyoshi
Kawabe, Tsutomu
Hasegawa, Yoshinori
Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers
title Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers
title_full Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers
title_fullStr Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers
title_full_unstemmed Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers
title_short Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers
title_sort hypoxia-induced modulation of pten activity and emt phenotypes in lung cancers
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836157/
https://www.ncbi.nlm.nih.gov/pubmed/27095949
http://dx.doi.org/10.1186/s12935-016-0308-3
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