Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis.
Animals
Benzylamines
/ pharmacology
Cell Nucleus
/ metabolism
Cell Transformation, Neoplastic
/ drug effects
Colitis-Associated Neoplasms
/ immunology
Disease Models, Animal
Epithelial Cells
Gastric Mucosa
/ cytology
Gastritis
/ immunology
Gerbillinae
Helicobacter Infections
/ immunology
Helicobacter pylori
/ immunology
Humans
Lipids
/ antagonists & inhibitors
Metaplasia
/ immunology
Mice
Mice, Transgenic
Organoids
Precancerous Conditions
/ drug therapy
Stomach Neoplasms
/ immunology
Chemoprevention
Colorectal cancer
Electrophiles
Stomach Cancer
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
17
07
2020
revised:
23
10
2020
accepted:
06
11
2020
pubmed:
16
11
2020
medline:
6
8
2021
entrez:
15
11
2020
Statut:
ppublish
Résumé
Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
Sections du résumé
BACKGROUND & AIMS
Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis.
METHODS
The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing.
RESULTS
We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity.
CONCLUSIONS
Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
Identifiants
pubmed: 33189701
pii: S0016-5085(20)35394-4
doi: 10.1053/j.gastro.2020.11.006
pmc: PMC7956217
mid: NIHMS1646966
pii:
doi:
Substances chimiques
Benzylamines
0
Lipids
0
isolevuglandin
0
2-(aminomethyl)phenol
932-30-9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1256-1268.e9Subventions
Organisme : NCI NIH HHS
ID : P01 CA028842
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190612
Pays : United States
Organisme : NIBIB NIH HHS
ID : U01 EB029242
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI142042
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK058404
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA116087
Pays : United States
Organisme : BLRD VA
ID : I01 BX001453
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA236733
Pays : United States
Organisme : NIH HHS
ID : S10 OD016245
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA068485
Pays : United States
Organisme : CSRD VA
ID : I01 CX002171
Pays : United States
Organisme : BLRD VA
ID : I01 BX004366
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK107960
Pays : United States
Informations de copyright
Published by Elsevier Inc.
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