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Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells

E McAdam, H. N Haboubi, G Forrester, Z Eltahir, S Spencer-Harty, C Davies, A. P Griffiths, J. N Baxter, G. J. S Jenkins, Gareth Jenkins Orcid Logo, Hasan Haboubi Orcid Logo

Carcinogenesis, Volume: 33, Start page: 2035

Swansea University Authors: Gareth Jenkins Orcid Logo, Hasan Haboubi Orcid Logo

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DOI (Published version): 10.1093/carcin/bgs241

Abstract

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signallin...

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Published in: Carcinogenesis
ISSN: 0143-3334 1460-2180
Published: 2012
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URI: https://cronfa.swan.ac.uk/Record/cronfa12373
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spelling 2019-06-24T15:31:04.6971261 v2 12373 2012-08-21 Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false f64fa85e00cad9a1523513becac836e0 0000-0001-7324-7889 Hasan Haboubi Hasan Haboubi true false 2012-08-21 BMS Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett’s esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids [deoxycholic acid (DCA)] can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF-κB activity. DCA-induced DNA damage was independent of NF-κB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF-κB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-κB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-κB activity (and possibly acid and DCA-induced NF-κB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-κB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-κB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus. Journal Article Carcinogenesis 33 2035 0143-3334 1460-2180 30 11 2012 2012-11-30 10.1093/carcin/bgs241 Accepted proof available online. Will be published late in 2012 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-06-24T15:31:04.6971261 2012-08-21T13:36:41.1339174 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine E McAdam 1 H. N Haboubi 2 G Forrester 3 Z Eltahir 4 S Spencer-Harty 5 C Davies 6 A. P Griffiths 7 J. N Baxter 8 G. J. S Jenkins 9 Gareth Jenkins 0000-0002-5437-8389 10 Hasan Haboubi 0000-0001-7324-7889 11
title Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
spellingShingle Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
Gareth Jenkins
Hasan Haboubi
title_short Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
title_full Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
title_fullStr Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
title_full_unstemmed Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
title_sort Inducible Nitric Oxide Synthase (iNOS) and Nitric Oxide (NO) are Important Mediators of Reflux-induced Cell Signalling in Esophageal Cells
author_id_str_mv a44095d26187304e903da7ca778697b6
f64fa85e00cad9a1523513becac836e0
author_id_fullname_str_mv a44095d26187304e903da7ca778697b6_***_Gareth Jenkins
f64fa85e00cad9a1523513becac836e0_***_Hasan Haboubi
author Gareth Jenkins
Hasan Haboubi
author2 E McAdam
H. N Haboubi
G Forrester
Z Eltahir
S Spencer-Harty
C Davies
A. P Griffiths
J. N Baxter
G. J. S Jenkins
Gareth Jenkins
Hasan Haboubi
format Journal article
container_title Carcinogenesis
container_volume 33
container_start_page 2035
publishDate 2012
institution Swansea University
issn 0143-3334
1460-2180
doi_str_mv 10.1093/carcin/bgs241
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
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description Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett’s esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids [deoxycholic acid (DCA)] can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF-κB activity. DCA-induced DNA damage was independent of NF-κB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF-κB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-κB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-κB activity (and possibly acid and DCA-induced NF-κB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-κB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-κB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus.
published_date 2012-11-30T03:14:19Z
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score 11.037603

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