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

Molecular Cancer

Research

Fenghua Lan¹  Junyong Han¹  Qiaojia Huang¹  Lihong Dong¹  Xiaoting Wang¹  Youdong Lin¹  Yanchuan Xie¹  Jianming Tan²  Lie Wang³  Xiaoli Yang³  Feng Zheng⁴  Xuenong Ouyang⁵  Han Wang⁵  Yinghao Yu⁶  Feilai Xie⁶  Wei Liu⁶ 

[1] Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, Fujian Province, Fuzhou City350025, China;Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, Fujian Province, Fuzhou City350025, China;Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, 350025, Fuzhou City, Fujian Province, China;Department of General Surgery, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, 350025, Fuzhou City, Fujian Province, China;Department of Nephrology, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, 350025, Fuzhou City, Fujian Province, China;Department of Oncology, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, 350025, Fuzhou City, Fujian Province, China;Department of Pathology, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, 350025, Fuzhou City, Fujian Province, China;

关键词: IL-1β;    p38;    Gastric adenocarcinoma;    MMP2 and MMP9;    AP-1;    Metastasis;   

DOI  :  10.1186/1476-4598-13-18

 received in 2013-09-07, accepted in 2014-01-21,  发布年份 2014

来源: Springer

【 摘 要 】

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-1(c-fos)/MMP2 & MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA.

【 授权许可】

CC BY   
© Huang et al.; licensee BioMed Central Ltd. 2014