Published in:
Open Access
01-12-2014 | Research
IL-1β-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9
Authors:
Qiaojia Huang, Fenghua Lan, Xiaoting Wang, Yinghao Yu, Xuenong Ouyang, Feng Zheng, Junyong Han, Youdong Lin, Yanchuan Xie, Feilai Xie, Wei Liu, Xiaoli Yang, Han Wang, Lihong Dong, Lie Wang, Jianming Tan
Published in:
Molecular Cancer
|
Issue 1/2014
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Abstract
Background
Interleukin-1β (IL-1β) has been implicated in the progression of gastric adenocarcinoma (GA); however, the molecular mechanisms of action of IL-1β in GA are poorly characterized. P38 and JNK are the major MAPK family members that regulate IL-1β signaling pathways. Here, we investigated the role of both p38 and JNK in IL-1β-induced GA cell migration, invasion and metastatic potential.
Methods
The effects of IL-1β-induced p38 and JNK activation in GA cells were determined using in vitro Transwell migration and invasion assays of MKN-45 and AGS cells, or an in vivo metastasis assay in nude mice. The IL-1β-induced p38 signaling pathway was further characterized in GA cells. Activation of the IL-1β/p38 signaling pathway was also assessed in human primary GA tissues by immunohistochemistry.
Results
IL-1β-induced activation of p38 increased GA cell migration and invasion in vitro and promoted the metastatic potential of GA cells in vivo; these effects were attenuated by p38 siRNA or the p38 inhibitor SB202190. MMP2 or MMP9 siRNAs and the MMP2/9 inhibitor BiPS also inhibited IL-1β-induced GA cell migration and invasion in vitro. IL-1β-induced p38 activation significantly increased MMP2 and MMP9 mRNA and protein expression and activity. Luciferase reporter assays demonstrated that the activator protein-1 (AP-1) and the AP-1 binding sites of the MMP9 promoter (−670/MMP9) were activated by IL-1β-induced p38 activation. Phospho-p38 was significantly upregulated in human GA tissues (compared to matched non-neoplastic tissues), and significantly associated with lymph node metastasis, and invasion beyond the serosa. Expression of phospho-p38 significantly correlated with IL-1β, MMP2, MMP9, and c-fos expression in both human GA tissues and GA cell metastases in the lungs of nude mice. IL-1β was also capable of activating JNK in GA cells, but activation of JNK was not associated with GA cell migration and invasion. Therefore, IL-1β-induced the migration and invasion in GA cells were regulated by p38, but not by JNK.
Conclusions
IL-1β-induced p38 activation and the IL-1β/p38/AP-1(c-fos)/MMP2 & MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA.