Abstract
BackgroundGastric cancer is the second most common cause of cancer-related death in the world. Inflammatory signals originating from gastric cancer cells are important for recruiting inflammatory cells and regulation of metastasis of gastric cancer. Several microRNAs (miRNA) have been shown to be involved in development and progression of gastric cancer. miRNA-146a (miR-146a) is a modulator of inflammatory signals, but little is known about its importance in gastric cancer. We therefore wanted to identify targets of miR-146a in gastric cancer and examine its biological roles.ResultsThe expression of miR-146a was evaluated by quantitative PCR (qPCR) and found up-regulated in the gastrin knockout mice, a mouse model of gastric cancer, and in 73% of investigated human gastric adenocarcinomas. Expression of miR-146a by gastric cancer cells was confirmed by in situ hybridization. Global analysis of changes in mRNA levels after miR-146a transfection identified two transcripts, caspase recruitment domain-containing protein 10 (CARD10) and COP9 signalosome complex subunit 8 (COPS8), as new miR-146a targets. qPCR, Western blotting and luciferase assays confirmed these transcripts as direct miR-146a targets. CARD10 and COPS8 were shown to be part of the G protein-coupled receptor (GPCR) pathway of nuclear factor-kappaB (NF-kappaB) activation. Lysophosphatidic acid (LPA) induces NF-kappaB activation via this pathway and over-expression of miR-146a inhibited LPA-induced NF-kappaB activation, reduced LPA-induced expression of tumor-promoting cytokines and growth factors and inhibited monocyte attraction.ConclusionsmiR-146a expression is up-regulated in a majority of gastric cancers where it targets CARD10 and COPS8, inhibiting GPCR-mediated activation of NF-kappaB, thus reducing expression of NF-kappaB-regulated tumor-promoting cytokines and growth factors. By targeting components of several NF-kappaB-activating pathways, miR-146a is a key component in the regulation of NF-kappaB activity.
Highlights
Gastric cancer is the second most common cause of cancer-related death in the world
Using quantitative PCR we found the expression of miR-146a app. 2-fold up-regulated in old gastrin KO mice with either fundic intestinal metaplasia or antral adenoma compared to the expression in wild type (WT) mice (P < 0.05) (Figure 1A)
Having established that miR-146a is increased in our mouse model of gastric cancer we examined expression of miR-146a in paired human gastric adenocarcinomas and adjacent control biopsies and found that it was up-regulated in 27 out of 37 cases (73%) (Figure 1B)
Summary
Gastric cancer is the second most common cause of cancer-related death in the world. Several microRNAs (miRNA) have been shown to be involved in development and progression of gastric cancer. MiRNA-146a (miR-146a) is a modulator of inflammatory signals, but little is known about its importance in gastric cancer. Gastric cancer is the second most common cause of cancer-related death [1]. Development of gastric cancer is influenced by interactions between host, environmental and bacterial factors. Examples of synergistic risk factors for gastric cancer are polymorphisms in genes involved in the host inflammatory response [2], Helicobacter pylori (H. pylori) virulence factors [3] and diets rich in salt and nitrate [4]. Inflammation leads to activation of the transcription factor nuclear factorkappaB (NF-κB), which is associated with gastric carcinogenesis [8,9]
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