Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling

Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to diseas...

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Bibliographic Details
Published in:Oncogene 2020-05, Vol.39 (22), p.4465-4474
Main Authors: Sierra, Johanna C, Piazuelo, M Blanca, Luis, Paula B, Barry, Daniel P, Allaman, Margaret M, Asim, Mohammad, Sebrell, Thomas A, Finley, Jordan L, Rose, Kristie L, Hill, Salisha, Holshouser, Steven L, Casero, Robert A, Cleveland, John L, Woster, Patrick M, Schey, Kevin L, Bimczok, Diane, Schneider, Claus, Gobert, Alain P, Wilson, Keith T
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - etiology
Adenocarcinoma - microbiology
Animals
beta Catenin - physiology
Carcinogenesis
Cell Transformation, Neoplastic
Deoxyribonucleic acid
Development and progression
DNA
DNA Damage
Gastric cancer
Gastric mucosa
Gastritis - enzymology
Gastritis - genetics
Gastritis - microbiology
Gastritis - pathology
Health aspects
Helicobacter infections
Helicobacter Infections - enzymology
Helicobacter Infections - genetics
Helicobacter Infections - pathology
Helicobacter pylori
Helicobacter pylori - pathogenicity
Hydrogen peroxide
Infection
Inflammation
Mice
Mice, Inbred C57BL
Mice, Knockout
Organoids
Oxidases
Oxidoreductases Acting on CH-NH Group Donors - deficiency
Oxidoreductases Acting on CH-NH Group Donors - genetics
Oxidoreductases Acting on CH-NH Group Donors - physiology
Polyamine Oxidase
Polyamines
Proteome
Risk factors
RNA, Messenger - biosynthesis
Signal Transduction
Spermidine
Spermidine - biosynthesis
Spermine
Spermine - metabolism
Stomach cancer
Stomach Neoplasms - etiology
Stomach Neoplasms - microbiology
β-Catenin
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Summary:Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus H O , is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-020-1304-6