Additive effects of EGF and IL-1β regulate tumor cell migration and invasion in gastric adenocarcinoma via activation of ERK1/2.
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.
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Junyong
J
Han
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Yanchuan
Y
Xie
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Fenghua
F
Lan
Department of Pathology, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Yinghao
Y
Yu
Department of Pathology, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Wei
W
Liu
Department of Medical Statistics, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Jinhua
J
Chen
Department of Nephrology and Central Laboratory, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Feng
F
Zheng
Department of Oncology, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Xuenong
X
Ouyang
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Xiangquan
X
Lin
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Yanhong
Y
Lin
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Qiaojia
Q
Huang
Department of General Surgery, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Lie
L
Wang
Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), Fuzhou, Fujian 350025, P.R. China.
Jianming
J
Tan
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D009570:Nitriles; D018808:Transcription Factor AP-1; C113580:U 0126; D004815:Epidermal Growth Factor; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9