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

Nature Communications 5, Article number: 4497 doi:10.1038/ncomms5497

Kotaro Kiga1,2*, Hitomi Mimuro1*, Masato Suzuki3, Aya Shinozaki-Ushiku4, Taira Kobayashi1, Takahito Sanada1, Minsoo Kim5, Michinaga Ogawa3, Yuka W. Iwasaki2, Hiroyuki Kayo2, Yoko Fukuda-Yuzawa2, Masakazu Yashiro6, Masashi Fukayama4, Taro Fukao2 & Chihiro Sasakawa3,5,7,8

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 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 Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. 6 Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. 7 Nippon Institute for Biological Science, 9-2221-1 Shinmachi, Ome, Tokyo 198-0024, Japan. 8 Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan. * These authors contributed equally to this work.

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.

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