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

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

Research output: Contribution to journalArticle

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.Oncogene advance online publication, 4 April 2016; doi:10.1038/onc.2016.91.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Apr 4 2016

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Epigenomics
Helicobacter pylori
Stomach Neoplasms
Gastritis
DNA Damage
Carcinogenesis
polyamine oxidase
Inflammation
Azacitidine
Messenger RNA
Polyamines
3' Untranslated Regions
DNA Methylation
MicroRNAs
Oncogenes
Hydrogen Peroxide
Methylation
Population
Genes
Publications

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Epigenetic silencing of miR-124 prevents spermine oxidase regulation : implications for Helicobacter pylori-induced gastric cancer. / Murray Stewart, Tracy; Sierra, J. C.; Piazuelo, M. B.; Mera, R. M.; Chaturvedi, R.; Bravo, L. E.; Correa, P.; Schneider, B. G.; Wilson, K. T.; Casero, Robert A.

In: Oncogene, 04.04.2016.

Research output: Contribution to journalArticle

Murray Stewart, Tracy ; Sierra, J. C. ; Piazuelo, M. B. ; Mera, R. M. ; Chaturvedi, R. ; Bravo, L. E. ; Correa, P. ; Schneider, B. G. ; Wilson, K. T. ; Casero, Robert A. / Epigenetic silencing of miR-124 prevents spermine oxidase regulation : implications for Helicobacter pylori-induced gastric cancer. In: Oncogene. 2016.
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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.Oncogene advance online publication, 4 April 2016; doi:10.1038/onc.2016.91.",
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AU - Mera, R. M.

AU - Chaturvedi, R.

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