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Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A

Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokin...

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Autores principales: Wu, Yongzhong, Meitzler, Jennifer L., Antony, Smitha, Juhasz, Agnes, Lu, Jiamo, Jiang, Guojian, Liu, Han, Hollingshead, Melinda, Haines, Diana C., Butcher, Donna, Panter, Michaela S., Roy, Krishnendu, Doroshow, James H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340089/
https://www.ncbi.nlm.nih.gov/pubmed/27637085
http://dx.doi.org/10.18632/oncotarget.12032
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author Wu, Yongzhong
Meitzler, Jennifer L.
Antony, Smitha
Juhasz, Agnes
Lu, Jiamo
Jiang, Guojian
Liu, Han
Hollingshead, Melinda
Haines, Diana C.
Butcher, Donna
Panter, Michaela S.
Roy, Krishnendu
Doroshow, James H.
author_facet Wu, Yongzhong
Meitzler, Jennifer L.
Antony, Smitha
Juhasz, Agnes
Lu, Jiamo
Jiang, Guojian
Liu, Han
Hollingshead, Melinda
Haines, Diana C.
Butcher, Donna
Panter, Michaela S.
Roy, Krishnendu
Doroshow, James H.
author_sort Wu, Yongzhong
collection PubMed
description Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H(2)O(2) production. To elucidate the pathophysiology of DUOX2-mediated H(2)O(2) formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H(2)O(2) which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-γ treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-γ-induced VEGF-A or HIF-1α up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human pre-malignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas.
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spelling pubmed-53400892017-03-08 Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A Wu, Yongzhong Meitzler, Jennifer L. Antony, Smitha Juhasz, Agnes Lu, Jiamo Jiang, Guojian Liu, Han Hollingshead, Melinda Haines, Diana C. Butcher, Donna Panter, Michaela S. Roy, Krishnendu Doroshow, James H. Oncotarget Research Paper Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H(2)O(2) production. To elucidate the pathophysiology of DUOX2-mediated H(2)O(2) formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H(2)O(2) which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-γ treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-γ-induced VEGF-A or HIF-1α up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human pre-malignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas. Impact Journals LLC 2016-09-15 /pmc/articles/PMC5340089/ /pubmed/27637085 http://dx.doi.org/10.18632/oncotarget.12032 Text en Copyright: © 2016 Wu 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wu, Yongzhong
Meitzler, Jennifer L.
Antony, Smitha
Juhasz, Agnes
Lu, Jiamo
Jiang, Guojian
Liu, Han
Hollingshead, Melinda
Haines, Diana C.
Butcher, Donna
Panter, Michaela S.
Roy, Krishnendu
Doroshow, James H.
Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
title Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
title_full Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
title_fullStr Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
title_full_unstemmed Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
title_short Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H(2)O(2)-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
title_sort dual oxidase 2 and pancreatic adenocarcinoma: ifn-γ-mediated dual oxidase 2 overexpression results in h(2)o(2)-induced, erk-associated up-regulation of hif-1α and vegf-a
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340089/
https://www.ncbi.nlm.nih.gov/pubmed/27637085
http://dx.doi.org/10.18632/oncotarget.12032
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