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Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer

Glucocorticoids (GCs) such as dexamethasone (DEX) are administered as cancer co-treatment for palliative purposes due to their pro-apoptotic effects in lymphoid cancer and limited side effects associated with cancer growth and chemotherapy. However, there is emerging evidence that GCs induce therapy...

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Autores principales: Abukiwan, Alia, Nwaeburu, Clifford C., Bauer, Nathalie, Zhao, Zhefu, Liu, Li, Gladkich, Jury, Gross, Wolfgang, Benner, Axel, Strobel, Oliver, Fellenberg, Jörg, Herr, Ingrid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255064/
https://www.ncbi.nlm.nih.gov/pubmed/30387838
http://dx.doi.org/10.3892/ijo.2018.4616
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author Abukiwan, Alia
Nwaeburu, Clifford C.
Bauer, Nathalie
Zhao, Zhefu
Liu, Li
Gladkich, Jury
Gross, Wolfgang
Benner, Axel
Strobel, Oliver
Fellenberg, Jörg
Herr, Ingrid
author_facet Abukiwan, Alia
Nwaeburu, Clifford C.
Bauer, Nathalie
Zhao, Zhefu
Liu, Li
Gladkich, Jury
Gross, Wolfgang
Benner, Axel
Strobel, Oliver
Fellenberg, Jörg
Herr, Ingrid
author_sort Abukiwan, Alia
collection PubMed
description Glucocorticoids (GCs) such as dexamethasone (DEX) are administered as cancer co-treatment for palliative purposes due to their pro-apoptotic effects in lymphoid cancer and limited side effects associated with cancer growth and chemotherapy. However, there is emerging evidence that GCs induce therapy resistance in most epithelial tumors. Our recent data reveal that DEX promotes the progression of pancreatic ductal adenocarcinoma (PDA). In the present study, we examined 1 primary and 2 established PDA cell lines, and 35 PDA tissues from patients who had received (n=14) or not received (n=21) GCs prior to surgery. Through microRNA microarray analysis, in silico, and RT-qPCR analyses, we identified 268 microRNAs differentially expressed between DEX-treated and untreated cells. With a focus on cancer progression, we selected miR-132 and its target gene, transforming growth factor-β2 (TGF-β2), as top candidates. miR-132 mimics directly bound to the 3′ untranslated region (3′UTR) of a TGF-β2 luciferase construct and enhanced expression, as shown by increased luciferase activity. By contrast, DEX inhibited miR-132 expression via promoter methylation. miR-132 mimics also reduced DEX-induced clonogenicity, migration and expression of vimentin and E-cadherin in vitro and in tumor xenografts. In patients, GC intake prior to surgery enhanced global hypermethylation and expression of TGF-β2 in tissues; expression of miR-132 was detected but could not be quantified. Our results demonstrate that DEX-mediated inhibition of miR-132 is a key mediator in the progression of pancreatic cancer, and the findings provide a foundation for miRNA-based therapies.
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spelling pubmed-62550642018-12-13 Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer Abukiwan, Alia Nwaeburu, Clifford C. Bauer, Nathalie Zhao, Zhefu Liu, Li Gladkich, Jury Gross, Wolfgang Benner, Axel Strobel, Oliver Fellenberg, Jörg Herr, Ingrid Int J Oncol Articles Glucocorticoids (GCs) such as dexamethasone (DEX) are administered as cancer co-treatment for palliative purposes due to their pro-apoptotic effects in lymphoid cancer and limited side effects associated with cancer growth and chemotherapy. However, there is emerging evidence that GCs induce therapy resistance in most epithelial tumors. Our recent data reveal that DEX promotes the progression of pancreatic ductal adenocarcinoma (PDA). In the present study, we examined 1 primary and 2 established PDA cell lines, and 35 PDA tissues from patients who had received (n=14) or not received (n=21) GCs prior to surgery. Through microRNA microarray analysis, in silico, and RT-qPCR analyses, we identified 268 microRNAs differentially expressed between DEX-treated and untreated cells. With a focus on cancer progression, we selected miR-132 and its target gene, transforming growth factor-β2 (TGF-β2), as top candidates. miR-132 mimics directly bound to the 3′ untranslated region (3′UTR) of a TGF-β2 luciferase construct and enhanced expression, as shown by increased luciferase activity. By contrast, DEX inhibited miR-132 expression via promoter methylation. miR-132 mimics also reduced DEX-induced clonogenicity, migration and expression of vimentin and E-cadherin in vitro and in tumor xenografts. In patients, GC intake prior to surgery enhanced global hypermethylation and expression of TGF-β2 in tissues; expression of miR-132 was detected but could not be quantified. Our results demonstrate that DEX-mediated inhibition of miR-132 is a key mediator in the progression of pancreatic cancer, and the findings provide a foundation for miRNA-based therapies. D.A. Spandidos 2018-11-01 /pmc/articles/PMC6255064/ /pubmed/30387838 http://dx.doi.org/10.3892/ijo.2018.4616 Text en Copyright: © Abukiwan et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Abukiwan, Alia
Nwaeburu, Clifford C.
Bauer, Nathalie
Zhao, Zhefu
Liu, Li
Gladkich, Jury
Gross, Wolfgang
Benner, Axel
Strobel, Oliver
Fellenberg, Jörg
Herr, Ingrid
Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer
title Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer
title_full Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer
title_fullStr Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer
title_full_unstemmed Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer
title_short Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer
title_sort dexamethasone-induced inhibition of mir-132 via methylation promotes tgf-β-driven progression of pancreatic cancer
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255064/
https://www.ncbi.nlm.nih.gov/pubmed/30387838
http://dx.doi.org/10.3892/ijo.2018.4616
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