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

Johanna C. Sierra, M. Blanca Piazuelo, Paula B. Luis, Daniel P. Barry, Margaret M. Allaman, Mohammad Asim, Thomas A. Sebrell, Jordan L. Finley, Kristie L. Rose, Salisha Hill, Steven L. Holshouser, Robert A. Casero, John L. Cleveland, Patrick M. Woster, Kevin L. Schey, Diane Bimczok, Claus Schneider, Alain P. Gobert, Keith T. Wilson

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 H2O2, 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.

Original languageEnglish (US)
Pages (from-to)4465-4474
Number of pages10
JournalOncogene
Volume39
Issue number22
DOIs
StatePublished - May 28 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint

Dive into the research topics of 'Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling'. Together they form a unique fingerprint.

Cite this