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microRNA-146a inhibits G protein-coupled receptor-mediated activation of NF-κB by targeting CARD10 and COPS8 in gastric cancer

Stephanie Geisler Crone1, Anders Jacobsen23, Birgitte Federspiel4, Linda Bardram5, Anders Krogh2, Anders H Lund6 and Lennart Friis-Hansen1*

  • * Corresponding author: Lennart Friis-Hansen lfh@rh.dk

Author Affiliations

1 Genomic Medicine, Rigshospitalet, University of Copenhagen, Rigshospitalet, Blegdamsvej 9, Copenhagen DK2100, Denmark

2 Bioinformatics Centre, Institute of Molecular Biology, University of Copenhagen, Copenhagen, Denmark

3 Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

4 Dept. of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

5 Dept. of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

6 BRIC - Biotech Research & Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark

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Molecular Cancer 2012, 11:71  doi:10.1186/1476-4598-11-71

Published: 20 September 2012

Abstract

Background

Gastric 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.

Results

The 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.

Conclusions

miR-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.

Keywords:
Stomach cancer; Non-coding RNA; Cytokines