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Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleoti...

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Autores principales: Mahmood, Badar, Damm, Morten Matthiesen Bach, Jensen, Thorbjørn Søren Rønn, Backe, Marie Balslev, Dahllöf, Mattias Salling, Poulsen, Steen Seier, Bindslev, Niels, Hansen, Mark Berner
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141637/
https://www.ncbi.nlm.nih.gov/pubmed/27927168
http://dx.doi.org/10.1186/s12885-016-2980-z
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author Mahmood, Badar
Damm, Morten Matthiesen Bach
Jensen, Thorbjørn Søren Rønn
Backe, Marie Balslev
Dahllöf, Mattias Salling
Poulsen, Steen Seier
Bindslev, Niels
Hansen, Mark Berner
author_facet Mahmood, Badar
Damm, Morten Matthiesen Bach
Jensen, Thorbjørn Søren Rønn
Backe, Marie Balslev
Dahllöf, Mattias Salling
Poulsen, Steen Seier
Bindslev, Niels
Hansen, Mark Berner
author_sort Mahmood, Badar
collection PubMed
description BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. METHODS: Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. RESULTS: In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. CONCLUSION: In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2980-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-51416372016-12-15 Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia Mahmood, Badar Damm, Morten Matthiesen Bach Jensen, Thorbjørn Søren Rønn Backe, Marie Balslev Dahllöf, Mattias Salling Poulsen, Steen Seier Bindslev, Niels Hansen, Mark Berner BMC Cancer Research Article BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. METHODS: Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. RESULTS: In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. CONCLUSION: In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2980-z) contains supplementary material, which is available to authorized users. BioMed Central 2016-12-07 /pmc/articles/PMC5141637/ /pubmed/27927168 http://dx.doi.org/10.1186/s12885-016-2980-z Text en © The Author(s). 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 Research Article
Mahmood, Badar
Damm, Morten Matthiesen Bach
Jensen, Thorbjørn Søren Rønn
Backe, Marie Balslev
Dahllöf, Mattias Salling
Poulsen, Steen Seier
Bindslev, Niels
Hansen, Mark Berner
Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
title Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
title_full Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
title_fullStr Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
title_full_unstemmed Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
title_short Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
title_sort phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141637/
https://www.ncbi.nlm.nih.gov/pubmed/27927168
http://dx.doi.org/10.1186/s12885-016-2980-z
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