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Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling

Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly types of malignancies because of its high ability to metastasize. PDAC is thought to be under hypoxic condition. Therefore, to investigate the mechanism of metastatic processes, chronic-hypoxia-resistant PDAC cells were newly generated...

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Autores principales: Morifuji, Yoshihiro, Onishi, Hideya, Iwasaki, Hironori, Imaizumi, Akira, Nakano, Kenji, Tanaka, Masao, Katano, Mitsuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317936/
https://www.ncbi.nlm.nih.gov/pubmed/24397700
http://dx.doi.org/10.1111/cas.12348
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author Morifuji, Yoshihiro
Onishi, Hideya
Iwasaki, Hironori
Imaizumi, Akira
Nakano, Kenji
Tanaka, Masao
Katano, Mitsuo
author_facet Morifuji, Yoshihiro
Onishi, Hideya
Iwasaki, Hironori
Imaizumi, Akira
Nakano, Kenji
Tanaka, Masao
Katano, Mitsuo
author_sort Morifuji, Yoshihiro
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly types of malignancies because of its high ability to metastasize. PDAC is thought to be under hypoxic condition. Therefore, to investigate the mechanism of metastatic processes, chronic-hypoxia-resistant PDAC cells were newly generated under hypoxic condition for 3–6 months and reoxygenation experiments were performed using these chronic-hypoxia-resistant PDAC cells in in vivo-mimicking conditions. Proliferation, invasiveness and tumorigenicity in PDAC cells were significantly increased by reoxygenation. A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation. Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9. Moreover, inhibition of Sonic Hh and Smoothened abrogated reoxygenation induced increases in proliferation and invasiveness. These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway. Therefore, the Hh signaling pathway may be a therapeutic target for refractory PDAC in metastatic processes induced by reoxygenation.
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spelling pubmed-43179362015-10-05 Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling Morifuji, Yoshihiro Onishi, Hideya Iwasaki, Hironori Imaizumi, Akira Nakano, Kenji Tanaka, Masao Katano, Mitsuo Cancer Sci Original Articles Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly types of malignancies because of its high ability to metastasize. PDAC is thought to be under hypoxic condition. Therefore, to investigate the mechanism of metastatic processes, chronic-hypoxia-resistant PDAC cells were newly generated under hypoxic condition for 3–6 months and reoxygenation experiments were performed using these chronic-hypoxia-resistant PDAC cells in in vivo-mimicking conditions. Proliferation, invasiveness and tumorigenicity in PDAC cells were significantly increased by reoxygenation. A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation. Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9. Moreover, inhibition of Sonic Hh and Smoothened abrogated reoxygenation induced increases in proliferation and invasiveness. These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway. Therefore, the Hh signaling pathway may be a therapeutic target for refractory PDAC in metastatic processes induced by reoxygenation. BlackWell Publishing Ltd 2014-03 2014-02-11 /pmc/articles/PMC4317936/ /pubmed/24397700 http://dx.doi.org/10.1111/cas.12348 Text en © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. http://creativecommons.org/licenses/by-nc/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial 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
Morifuji, Yoshihiro
Onishi, Hideya
Iwasaki, Hironori
Imaizumi, Akira
Nakano, Kenji
Tanaka, Masao
Katano, Mitsuo
Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling
title Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling
title_full Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling
title_fullStr Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling
title_full_unstemmed Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling
title_short Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling
title_sort reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the hedgehog signaling
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317936/
https://www.ncbi.nlm.nih.gov/pubmed/24397700
http://dx.doi.org/10.1111/cas.12348
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