Interleukin 1 upregulates microRNA-135b to promote inflammation-associated gastric carcinogenesis in mice.

フォーマット:

論文

責任表示:

Tae, Su Han ; Voon, Dominic Chih-Cheng ; Oshima, Hiroko ; Nakayama, Mizuho ; Echizen, Kanae ; Sakai, Eri ; Yong, Zachary Wei Ern ; Murakami, Kazuhiro ; Yu, Liang ; Minamoto, Toshinari ; Ock, Chan-Young ; Jenkins, Brendan J. ; Kim, Seong-Jin ; Yang, Han-Kwang ; Oshima, Masanobu ; 大島, 浩子 ; 中山, 瑞穂 ; 村上, 和弘 ; 源, 利成 ; 大島, 正伸

言語:

英語

出版情報:

Elsevier, 2019-03

著者名:

Tae, Su Han

Voon, Dominic Chih-Cheng

Oshima, Hiroko

Nakayama, Mizuho

Echizen, Kanae

Sakai, Eri

Yong, Zachary Wei Ern

Murakami, Kazuhiro

Yu, Liang

Minamoto, Toshinari

Ock, Chan-Young

Jenkins, Brendan J.

Kim, Seong-Jin

Yang, Han-Kwang

Oshima, Masanobu

大島, 浩子

中山, 瑞穂

村上, 和弘

源, 利成

大島, 正伸

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掲載情報:

Gastroenterology

ISSN:

0016-5085      

巻:

156

通号:

4

開始ページ:

1140

終了ページ:

1155

バージョン:

author

概要:

金沢大学ナノ生命科学研究所<br />Background & Aims: Gastritis is associated with development of stomach cancer, but little is known about changes in microRNA expression patterns during gastric inflammation. Specific changes in gene expression i … n epithelial cells are difficult to monitor because of the heterogeneity of the tissue. We investigated epithelial cell-specific changes in microRNA expression during gastric inflammation and gastritis-associated carcinogenesis in mice. Methods: We used laser microdissection to enrich epithelial cells from K19-C2mE transgenic mice, which spontaneously develop gastritis-associated hyperplasia, and Gan mice, which express activated prostaglandin E2 and Wnt in the gastric mucosa and develop gastric tumors. We measured expression of epithelial cell-enriched microRNAs and used bioinformatics analyses to integrate data from different systems to identify inflammation-associated microRNAs. We validated our findings in gastric tissues from mice and evaluated protein functions in gastric cell lines (SNU-719, SNU-601, SNU-638, AGS, and GIF-14) and knockout mice. Organoids were cultured from gastric corpus tissues of wild-type and miR-135b–knockout C57BL/6 mice. We measured levels of microRNAs in pairs of gastric tumors and nontumor mucosa from 28 patients in Japan. Results: We found microRNA 135b (miR-135B) to be the most overexpressed microRNA in gastric tissues from K19-C2mE and Gan mice: levels increased during the early stages of gastritis-associated carcinogenesis. Levels of miR-135B were also increased in gastric tumor tissues from gp130 F/F mice and patients compared with nontumor tissues. In gastric organoids and immortalized cell lines, expression of miR-135B was induced by interleukin 1 signaling. K19-C2mE mice with disruption of Mir-135b developed hyperplastic lesions that were 50% smaller than mice without Mir-135b disruption and had significant reductions in cell proliferation. Expression of miR-135B in gastric cancer cell lines increased their colony formation, migration, and sphere formation. We identified FOXN3 and RECK messenger RNAs (mRNAs) as targets of miR-135B; their knockdown reduced migration of gastric cancer cell lines. Levels of FOXN3 and RECK mRNAs correlated inversely with levels of miR-135B in human gastric tumors and in inflamed mucosa from K19-C2mE mice. Conclusions: We found expression of miR-135B to be up-regulated by interleukin L1 signaling in gastric cancer cells and organoids. miR-135B promotes invasiveness and stem-cell features of gastric cancer cells in culture by reducing FOXN3 and RECK messenger RNAs. Levels of these messenger RNA targets, which encode tumor suppressor, are reduced in human gastric tumors. © 2019 AGA Institute<br />Embargo Period 12 months 続きを見る

URL:

http://hdl.handle.net/2297/00053859