Document Detail


Glutathione peroxidase 7 protects against oxidative DNA damage in oesophageal cells.
MedLine Citation:
PMID:  22157330     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Exposure of the oesophageal mucosa to gastric acid and bile acids leads to the accumulation of reactive oxygen species (ROS), a known risk factor for Barrett's oesophagus and progression to oesophageal adenocarcinoma (OAC). This study investigated the functions of glutathione peroxidase 7 (GPX7), frequently silenced in OAC, and its capacity in regulating ROS and its associated oxidative DNA damage.
DESIGN: Using in-vitro cell models, experiments were performed that included glutathione peroxidase (GPX) activity, Amplex UltraRed, CM-H(2)DCFDA, Annexin V, 8-oxoguanine, phospho-H2A.X, quantitative real-time PCR and western blot assays.
RESULTS: Enzymatic assays demonstrated limited GPX activity of the recombinant GPX7 protein. GPX7 exhibited a strong capacity to neutralise hydrogen peroxide (H(2)O(2)) independent of glutathione. Reconstitution of GPX7 expression in immortalised Barrett's oesophagus cells, BAR-T and CP-A led to resistance to H(2)O(2)-induced oxidative stress. Following exposure to acidic bile acids cocktail (pH4), these GPX7-expressing cells demonstrated lower levels of H(2)O(2), intracellular ROS, oxidative DNA damage and double-strand breaks, compared with controls (p<0.01). In addition, these cells demonstrated lower levels of ROS signalling, indicated by reduced phospho-JNK (Thr183/Tyr185) and phospho-p38 (Thr180/Tyr182), and demonstrated lower levels of apoptosis following the exposure to acidic bile acids or H(2)O(2)-induced oxidative stress. The knockdown of endogenous GPX7 in immortalised oesophageal squamous epithelial cells (HET1A) confirmed the protective functions of GPX7 against pH4 bile acids by showing an increase in the levels of H(2)O(2), intracellular ROS, oxidative DNA damage, double-strand breaks, apoptosis, and ROS-dependent signalling (p<0.01).
CONCLUSION: The dysfunction of GPX7 in oesophageal cells increases the levels of ROS and oxidative DNA damage, which are common risk factors for Barrett's oesophagus and OAC.
Authors:
Dunfa Peng; Abbes Belkhiri; Tianling Hu; Rupesh Chaturvedi; Mohammad Asim; Keith T Wilson; Alexander Zaika; Wael El-Rifai
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-09
Journal Detail:
Title:  Gut     Volume:  61     ISSN:  1468-3288     ISO Abbreviation:  Gut     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-14     Completed Date:  2012-11-06     Revised Date:  2013-12-09    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  1250-60     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / enzymology,  physiopathology
Barrett Esophagus / enzymology*,  physiopathology
Bile Acids and Salts / adverse effects
Blotting, Western
Cell Line
DNA Damage / physiology*
Disease Progression
Epithelial Cells / enzymology
Esophageal Neoplasms / enzymology,  physiopathology
Esophagus / cytology,  enzymology*,  pathology
Flow Cytometry
Gene Expression Regulation
Glutathione Peroxidase / genetics,  metabolism,  physiology*
Humans
Hydrogen Peroxide / metabolism
Oxidative Stress / physiology
Reactive Oxygen Species / metabolism*
Grant Support
ID/Acronym/Agency:
DK058404/DK/NIDDK NIH HHS; P30 CA68485/CA/NCI NIH HHS; P50 CA95103/CA/NCI NIH HHS; R01 CA106176/CA/NCI NIH HHS; R01 CA106176-10/CA/NCI NIH HHS; R01 CA138833/CA/NCI NIH HHS; R01 DK053620/DK/NIDDK NIH HHS; R01CA106176/CA/NCI NIH HHS; R01CA138833/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Reactive Oxygen Species; BBX060AN9V/Hydrogen Peroxide; EC 1.11.1.9/Glutathione Peroxidase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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