Epigenetic silencing of miR-124 prevents spermine oxidase regulation: Implications for Helicobacter pylori-induced gastric cancer

T. Murray-Stewart, J. C. Sierra, M. B. Piazuelo, R. M. Mera, R. Chaturvedi, L. E. Bravo, P. Correa, B. G. Schneider, K. T. Wilson, R. A. Casero

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic inflammation contributes to the development of various forms of cancer. The polyamine catabolic enzyme spermine oxidase (SMOX) is induced in chronic inflammatory conditions, including Helicobacter pylori-associated gastritis, where its production of hydrogen peroxide contributes to DNA damage and subsequent tumorigenesis. MicroRNA expression levels are also altered in inflammatory conditions; specifically, the tumor suppressor miR-124 becomes silenced by DNA methylation. We sought to determine if this repression of miR-124 is associated with elevated SMOX activity and concluded that miR-124 is indeed a negative regulator of SMOX. In gastric adenocarcinoma cells harboring highly methylated and silenced mir-124 gene loci, 5-azacytidine treatment allowed miR-124 re-expression and decreased SMOX expression. Overexpression of an exogenous miR-124-3p mimic repressed SMOX mRNA and protein expression as well as H2O2 production by >50% within 24 h. Reporter assays indicated that direct interaction of miR-124 with the 3′-untranslated region of SMOX mRNA contributes to this negative regulation. Importantly, overexpression of miR-124 before infection with H. pylori prevented the induction of SMOX believed to contribute to inflammation-associated tumorigenesis. Compelling human in vivo data from H. pylori-positive gastritis tissues indicated that the mir-124 gene loci are more heavily methylated in a Colombian population characterized by elevated SMOX expression and a high risk for gastric cancer. Furthermore, the degree of mir-124 methylation significantly correlated with SMOX expression throughout the population. These results indicate a protective role for miR-124 through the inhibition of SMOX-mediated DNA damage in the etiology of H. pylori-associated gastric cancer.

Original languageEnglish (US)
Pages (from-to)5480-5488
Number of pages9
JournalOncogene
Volume35
Issue number42
DOIs
StatePublished - Oct 20 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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