Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice
2019
Background & Aims
Gastritisis associated with development of
stomach cancer, but little is known about changes in
microRNAexpression 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
microRNAexpression 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
microRNAsand 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.
Organoidswere cultured from gastric corpus tissues of wild-type and miR-135b–knockout C57BL/6 mice. We measured levels of
microRNAsin pairs of gastric tumors and nontumor mucosa from 28 patients in Japan. Results We found
microRNA135b (miR-135B) to be the most overexpressed
microRNAin 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
organoidsand 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.
Levelsof 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 RNAtargets, which encode tumor suppressor, are reduced in human gastric tumors.
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