IL-1β-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1-c-fos, MMP2 and MMP9Report as inadecuate

IL-1β-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1-c-fos, MMP2 and MMP9 - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 13:18

First Online: 31 January 2014Received: 07 September 2013Accepted: 21 January 2014DOI: 10.1186-1476-4598-13-18

Cite this article as: Huang, Q., Lan, F., Wang, X. et al. Mol Cancer 2014 13: 18. doi:10.1186-1476-4598-13-18


BackgroundInterleukin-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.

MethodsThe 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.

ResultsIL-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.

ConclusionsIL-1β-induced p38 activation and the IL-1β-p38-AP-1c-fos-MMP2 and MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA.

KeywordsIL-1β p38 Gastric adenocarcinoma MMP2 and MMP9 AP-1 Metastasis Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-18 contains supplementary material, which is available to authorized users.

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Author: Qiaojia Huang - Fenghua Lan - Xiaoting Wang - Yinghao Yu - Xuenong Ouyang - Feng Zheng - Junyong Han - Youdong Lin - Yanch


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