Additive effects of EGF and IL-1β regulate tumor cell migration and invasion in gastric adenocarcinoma via activation of ERK1/2

Han,Junyong; Xie,Yanchuan; Lan,Fenghua; Yu,Yinghao; Liu,Wei; Chen,Jinhua; Zheng,Feng; Ouyang,Xuenong; Lin,Xiangquan; Lin,Yanhong; Huang,Qiaojia; Wang,Lie; Tan,Jianming

doi:10.3892/ijo.2014.2401

Additive effects of EGF and IL-1β regulate tumor cell migration and invasion in gastric adenocarcinoma via activation of ERK1/2

Authors:
- Junyong Han
- Yanchuan Xie
- Fenghua Lan
- Yinghao Yu
- Wei Liu
- Jinhua Chen
- Feng Zheng
- Xuenong Ouyang
- Xiangquan Lin
- Yanhong Lin
- Qiaojia Huang
- Lie Wang
- Jianming Tan
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Affiliations: Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China, Department of Pathology, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China, Department of Medical Statistics, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China, Department of Nephrology and Central Laboratory, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China, Department of Oncology, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China, Department of General Surgery, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China
Published online on: April 28, 2014 https://doi.org/10.3892/ijo.2014.2401
Pages: 291-301

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Abstract

Growth and inflammatory factors are associated with poor prognosis in gastric adenocarcinoma (GA); however, the additive effects of growth and inflammatory factors in GA remain unclear. In this study, we investigated the ability of epidermal growth factor (EGF) and interleukin (IL‑1β) to activate extracellular signal-regulated kinase (ERK)1/2 in GA cells, and correlated the relationships between their roles with the metastatic potential both in GA cells and GA tissues. The effects of EGF, IL-1β and EGF plus IL-1β in AGS and MKN-45 GA cells were examined using western blotting, Transwell migration and invasion assays, immunocytochemical staining and an activator protein (AP)-1 luciferase reporter gene assay, and was further characterized in GA tissues by immunohistochemistry. The results exhibited that EGF and IL-1β additively activated ERK1/2, increased migration and invasion than either EGF or IL-1β alone in AGS and MKN-45 cells. The mechanisms were involved in upregulating MMP-9 expression through increasing AP-1 transcriptional activity via ERK1/2 pathway; these effects were dose-dependently inhibited by silencing ERK1/2 or using U0126. In vivo data also confirmed that the overexpression of p-ERK1/2 in GA tissues correlated well with the EGF, IL-1β, EGF plus IL-1β, and was associated with metastasis, which was well correlation with the expression of MMP-9 and c-fos (AP-1). The results demonstrate that growth and inflammatory factors play an important role in metastasis of GA by additively activating ERK-1/2 and AP-1, and upregulating MMP-9. As both cytokines contribute to the migration and invasion of GA cells, EGF/IL-1β/ERK1/2 pathways may be key pathways closely associated with GA progression.

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