IL-1[beta]-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9

Background Interleukin-1[beta] (IL-1[beta]) has been implicated in the progression of gastric adenocarcinoma (GA); however, the molecular mechanisms of action of IL-1[beta] in GA are poorly characterized. P38 and JNK are the major MAPK family members that regulate IL-1[beta] signaling pathways. Here, we investigated the role of both p38 and JNK in IL-1[beta]-induced GA cell migration, invasion and metastatic potential. Methods The effects of IL-1[beta]-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-1[beta]-induced p38 signaling pathway was further characterized in GA cells. Activation of the IL-1[beta]/p38 signaling pathway was also assessed in human primary GA tissues by immunohistochemistry. Results IL-1[beta]-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-1[beta]-induced GA cell migration and invasion in vitro. IL-1[beta]-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-1[beta]-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-1[beta], MMP2, MMP9, and c-fos expression in both human GA tissues and GA cell metastases in the lungs of nude mice. IL-1[beta] was also capable of activating JNK in GA cells, but activation of JNK was not associated with GA cell migration and invasion. Therefore, IL-1[beta]-induced the migration and invasion in GA cells were regulated by p38, but not by JNK. Conclusions IL-1[beta]-induced p38 activation and the IL-1[beta]/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. Keywords: IL-1[beta], p38, Gastric adenocarcinoma, MMP2 and MMP9, AP-1, Metastasis