title: Epigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection.
abstract: Persistent colonization of the gastric mucosa by Helicobacter pylori (Hp) elicits chronic inflammation and aberrant epithelial cell proliferation, which increases the risk of gastric cancer. Here we examine the ability of microRNAs to modulate gastric cell proliferation in response to persistent Hp infection and find that epigenetic silencing of miR-210 plays a key role in gastric disease progression. Importantly, DNA methylation of the miR-210 gene is increased in Hp-positive human gastric biopsies as compared with Hp-negative controls. Moreover, silencing of miR-210 in gastric epithelial cells promotes proliferation. We identify STMN1 and DIMT1 as miR-210 target genes and demonstrate that inhibition of miR-210 expression augments cell proliferation by activating STMN1 and DIMT1. Together, our results highlight inflammation-induced epigenetic silencing of miR-210 as a mechanism of induction of chronic gastric diseases, including cancer, during Hp infection.
authors.affiliation: 1] Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2] Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany [3].
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kiga
authors.affiliation: 1] Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2].
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Shinozaki-Ushiku
authors.affiliation: Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Taira
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Sanada
authors.affiliation: Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Michinaga
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Yuka W
authors.initials: YW
authors.lastname: Iwasaki
authors.affiliation: Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kayo
authors.affiliation: Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda-Yuzawa
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Taro
authors.initials: T
authors.lastname: Fukao
authors.affiliation: 1] Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2] Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan [3] Nippon Institute for Biological Science, 9-2221-1 Shinmachi, Ome, Tokyo 198-0024, Japan [4] Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002908:Chronic Disease; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000150:complications / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
chemical_list: C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C493995:STMN1 protein, human; D050777:Stathmin; D008780:Methyltransferases; C047346:16S rRNA (adenine(1518)-N(6)-adenine(1519)-N(6))-dimethyltransferase