Epigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection

Kotaro Kiga; Hitomi Mimuro; Masato Suzuki; Aya Shinozaki-Ushiku; Taira Kobayashi; Takahito Sanada; Minsoo Kim; Michinaga Ogawa; Yuka W Iwasaki; Hiroyuki Kayo; Yoko Fukuda-Yuzawa; Masakazu Yashiro; Masashi Fukayama; Taro Fukao; Chihiro Sasakawa

doi:10.1038/ncomms5497

Epigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection

Nat Commun. 2014 Sep 4:5:4497. doi: 10.1038/ncomms5497.

Authors

Affiliations

¹ 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].
² 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].
³ Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁴ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
⁵ 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.
⁶ Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁷ Max-Planck-Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
⁸ Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
⁹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle / genetics
Cell Proliferation
Chronic Disease
DNA Methylation
Epigenesis, Genetic*
Epithelial Cells / metabolism
Epithelial Cells / microbiology
Epithelial Cells / pathology
Gastric Mucosa / metabolism
Gastric Mucosa / microbiology
Gastric Mucosa / pathology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Gerbillinae
Helicobacter Infections / complications
Helicobacter Infections / genetics*
Helicobacter Infections / microbiology
Helicobacter Infections / pathology
Helicobacter pylori / pathogenicity
Helicobacter pylori / physiology
Humans
Male
Methyltransferases / genetics
Methyltransferases / metabolism*
MicroRNAs / antagonists & inhibitors
MicroRNAs / genetics
MicroRNAs / metabolism*
Oligonucleotide Array Sequence Analysis
Primary Cell Culture
Promoter Regions, Genetic
Protein Binding
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Stathmin / genetics
Stathmin / metabolism*
Stomach Neoplasms / complications
Stomach Neoplasms / genetics*
Stomach Neoplasms / microbiology
Stomach Neoplasms / pathology

Substances

MIRN210 microRNA, human
MicroRNAs
RNA, Small Interfering
STMN1 protein, human
Stathmin
Methyltransferases
16S rRNA (adenine(1518)-N(6)-adenine(1519)-N(6))-dimethyltransferase

Associated data

GEO/GSE58004