Store-operated Ca2+ Entry Facilitates the Lipopolysaccharide-induced Cyclooxygenase-2 Expression in Gastric Cancer Cells

Jhen-Hong Wong,Jaw-Yuan Wang,Che-Mai Chang,Kuo-Hao Ho,Wei-Chiao Chang,Wen-Li Hsu,Chia-Hsien Lin,Sean Nam

doi:10.1038/s41598-017-12648-1

Abstract

Helicobacter pylori has been identified as one of the major causes of chronic gastritis, gastric and duodenal ulcers, and gastric cancer. Lipopolysaccharide (LPS) is a major component of the outer membrane of gram-negative bacteria, and H. pylori LPS might play an exclusively important role in activating inflammatory pathways in monocytes and macrophages. To study the role of LPS in the underlying mechanism of inflammatory responses, we established an in vitro model using the human AGS gastric cancer cell line. We found that LPS mediates inflammation through setting off a cascade of events: activation of the store-operated calcium (SOC) channel, initiation of downstream NF-κB signaling, and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Phosphorylated ERK1/2 promotes the nuclear translocation of NF-κB, and eventually elevates the expression level of COX-2, a major inflammatory gene.

Highlights

LPS, known as endotoxin, displays robust immunostimulatory abilities upon recognition by toll-like receptor 4/MD-211
To determine the role of LPS in COX-2 gene regulation, AGS cells were treated with 10 ng/mL LPS
H. pylori infections are more widespread in developing countries, which are often plagued by water pollution and unsanitary living conditions

Summary

Introduction

LPS, known as endotoxin, displays robust immunostimulatory abilities upon recognition by toll-like receptor 4/MD-211. Research groups suggested that the structures of H. pylori LPS and lipid A can modulate immune responses during infection, and both play roles in chronic inflammatory responses[13,14,15,16]. COX-2 is an inducible enzyme that plays a key role in the synthesis of prostaglandins in response to inflammatory stimuli. COX-2 gene expression was found to respond to other stimuli, including growth factors, endotoxin, carcinogen, hormones, and chemokines[21]. We report on interactions and the hierarchy of elements involved in COX-2 gene activation in AGS cells. Our results substantiate that the store-operated calcium (SOC) channel, extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) are necessary mediators of LPS-induced COX-2 gene expression in GC

Methods

Results

Conclusion