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

Oncogene volume 39, pages 4465–4474 (2020)Cite this article

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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.

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Fig. 1: Smox expression and polyamine concentrations in gastric tissues and murine gastroids.
Fig. 2: H. pylori-induced gastritis in C57BL/6 WT and Smox−/− mice.
Fig. 3: Effect of Smox deletion on H. pylori-stimulated GECs derived from gastric organoids.
Fig. 4: Effect of SMOX activity on β-catenin activation in human-derived gastric organoids.

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Acknowledgements

This work was funded by NIH grants R01CA190612 (K.T.W.), P01CA116087 (K.T.W.), P01CA028842 (K.T.W.), and R21AI142042 (K.T.W.); Veterans Affairs Merit Review grant I01BX001453 (K.T.W.); Department of Defense grant W81XWH-18-1-0301 (K.T.W.); the Thomas F. Frist Sr. Endowment (K.T.W.); and the Vanderbilt Center for Mucosal Inflammation and Cancer (K.T.W.). This work was also supported by NIH grants R01AT006896 (C.S.), R03DK107960 (D.B.), R01GM131408 (D.B.), R01CA204345 (R.A.C. and P.M.W.), R01CA235863 (R.A.C.), and R01CA100603 (J.L.C.). J.L.C. was also supported by the Cortner-Couch Endowed Chair for Cancer Research from the University of South Florida (J.L.C.) and NCI Comprehensive Cancer Grant P30CA76292 to the H. Lee Moffitt Cancer Center and Research Institute. P.B.L. was supported by a postdoctoral fellowship award from the American Heart Association (16POST27250138). Mass spectrometry analyses were supported in part by Core Scholarships from the Vanderbilt University Medical Center Digestive Disease Research Center funded by NIH grant P30DK058404, and the Vanderbilt Ingram Cancer Center support grant P30CA068485. Immunofluorescence confocal imaging was performed in the Vanderbilt Cell Imaging Shared Resource, supported by the Vanderbilt Digestive Disease Research Center and NIH grant P30DK058404.

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Johanna C. Sierra, M. Blanca Piazuelo, Daniel P. Barry, Margaret M. Allaman, Mohammad Asim, Jordan L. Finley, Alain P. Gobert & Keith T. Wilson

  2. Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Johanna C. Sierra, M. Blanca Piazuelo, Claus Schneider, Alain P. Gobert & Keith T. Wilson

  3. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Paula B. Luis & Claus Schneider

  4. Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA

    Thomas A. Sebrell & Diane Bimczok

  5. Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Kristie L. Rose, Salisha Hill & Kevin L. Schey

  6. Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA

    Steven L. Holshouser & Patrick M. Woster

  7. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21287, USA

    Robert A. Casero

  8. Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    John L. Cleveland

  9. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Keith T. Wilson

  10. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, 37232, USA

    Keith T. Wilson

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Correspondence to Keith T. Wilson.

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Sierra, J.C., Piazuelo, M.B., Luis, P.B. et al. Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling. Oncogene 39, 4465–4474 (2020). https://doi.org/10.1038/s41388-020-1304-6

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