Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice

Tae Su Han, Dominic Chih Cheng Voon, Hiroko Oshima, Mizuho Nakayama, Kanae Echizen, Eri Sakai, Zachary Wei Ern Yong, Kazuhiro Murakami, Liang Yu, Toshinari Minamoto, Chan Young Ock, Brendan J. Jenkins, Seong Jin Kim, Han Kwang Yang, Masanobu Oshima

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 in 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.

Original languageEnglish
Pages (from-to)1140-1155.e4
Number of pages20
JournalGastroenterology
Volume156
Issue number4
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • Carcinogenesis
  • Oncogene
  • Stomach Cancer
  • Tumor Progression

Cite this

Han, T. S., Voon, D. C. C., Oshima, H., Nakayama, M., Echizen, K., Sakai, E., ... Oshima, M. (2019). Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice. Gastroenterology, 156(4), 1140-1155.e4. https://doi.org/10.1053/j.gastro.2018.11.059
Han, Tae Su ; 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. / Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice. In: Gastroenterology. 2019 ; Vol. 156, No. 4. pp. 1140-1155.e4.
@article{7a64070c0c9047b9bdcdff3853c34d79,
title = "Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice",
abstract = "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 in 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.",
keywords = "Carcinogenesis, Oncogene, Stomach Cancer, Tumor Progression",
author = "Han, {Tae Su} and Voon, {Dominic Chih Cheng} and Hiroko Oshima and Mizuho Nakayama and Kanae Echizen and Eri Sakai and Yong, {Zachary Wei Ern} and Kazuhiro Murakami and Liang Yu and Toshinari Minamoto and Ock, {Chan Young} and Jenkins, {Brendan J.} and Kim, {Seong Jin} and Yang, {Han Kwang} and Masanobu Oshima",
year = "2019",
month = "3",
day = "1",
doi = "10.1053/j.gastro.2018.11.059",
language = "English",
volume = "156",
pages = "1140--1155.e4",
journal = "Gastroenterology",
issn = "0016-5085",
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Han, TS, Voon, DCC, Oshima, H, Nakayama, M, Echizen, K, Sakai, E, Yong, ZWE, Murakami, K, Yu, L, Minamoto, T, Ock, CY, Jenkins, BJ, Kim, SJ, Yang, HK & Oshima, M 2019, 'Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice', Gastroenterology, vol. 156, no. 4, pp. 1140-1155.e4. https://doi.org/10.1053/j.gastro.2018.11.059

Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice. / Han, Tae Su; 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.

In: Gastroenterology, Vol. 156, No. 4, 01.03.2019, p. 1140-1155.e4.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice

AU - Han, Tae Su

AU - Voon, Dominic Chih Cheng

AU - Oshima, Hiroko

AU - Nakayama, Mizuho

AU - Echizen, Kanae

AU - Sakai, Eri

AU - Yong, Zachary Wei Ern

AU - Murakami, Kazuhiro

AU - Yu, Liang

AU - Minamoto, Toshinari

AU - Ock, Chan Young

AU - Jenkins, Brendan J.

AU - Kim, Seong Jin

AU - Yang, Han Kwang

AU - Oshima, Masanobu

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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 in 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.

AB - 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 in 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.

KW - Carcinogenesis

KW - Oncogene

KW - Stomach Cancer

KW - Tumor Progression

UR - http://www.scopus.com/inward/record.url?scp=85062415132&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2018.11.059

DO - 10.1053/j.gastro.2018.11.059

M3 - Article

VL - 156

SP - 1140-1155.e4

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -