title: Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer.
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 H2O2production 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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Murray-Stewart
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Sierra
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Mera
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.|Jawaharlal Nehru University School of Biotechnology, New Delhi, India.
authors.forename: R
authors.initials: R
authors.lastname: Chaturvedi
authors.affiliation: Department of Pathology, Universidad del Valle School of Medicine, Cali, Colombia.
authors.forename: L E
authors.initials: LE
authors.lastname: Bravo
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Correa
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Schneider
authors.affiliation: Vanderbilt University Medical Center, Division of Gastroenterology, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Casero
mesh_terms: D020413:3' Untranslated Regions; D001706:Biopsy; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005756:Gastritis / Q000209:etiology / Q000473:pathology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D013274:Stomach Neoplasms / Q000209:etiology / Q000473:pathology; D000097667:Polyamine Oxidase
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000097667:Polyamine Oxidase; C509207:MIRN124 microRNA, human