Abstract 2814: Sonic hedgehog in gastric cancer metastasis; MAP Kinase/NFκB-dependent signaling pathway.

Abstract

Abstract Up-regulation of Sonic hedgehog and their receptors by tumor is an important hallmark in cancer progression, as it contributes through autocrine and paracrine mechanisms to tumor development, invasion, and metastasis, but the role and cellular mechanism in the invasive phenotype of gastric cancer cells is not known. Herein, we determined the roles of Mitogen-activated protein kinase (MAPK) signaling, nuclear factor (NF)-κB, and matrix metalloproteinase (MMP) expression in Shh-mediated metastatic function in gastric cancer. We found that stimulation of Shh in gastric cancer cells enhanced the phosphorylation of JNK and p38. Accompanying activation of JNK and p38 kinase, Shh also enhanced phosphorylation/degradation of IκBα and the nuclear translocation/activation of NF-κB. Interestingly, blockade of JNK and p38 signaling using SP600125 and SB202190, respectively, significantly inhibited Shh-induced motility and invasiveness in association with the activation of NF-κB. In addition, phosphorylation of JNK, p38 and of IκBα, IκBα degradation, and the nuclear translocation of NF-κB was enhanced by treatment with N-shh, but not cyclopamin or shh neutralization antibodies. Furthermore, Shh-induced MMP-9 expression and enzymatic activity was also significantly blocked by treatment with MAPK, JNK, or NF-κB inhibitors. Immunohistochemistry staining of 178 gastric tumor biopsies indicated that expression of shh and MMP-9 had a significant positive correlation with lymph node metastasis and a poor prognosis. These results indicate that the Shh signaling pathway enhances tumor metastasis in gastric cancer by sequential activation of the JNK or MAPK pathway followed by the induction of NF-κB and MMP-9 activity, indicating that shh has the potential to be a therapeutic molecular target to decrease metastasis. Overall, our studies suggest that Shh promote motility and invasion of gastric cancer cells by activating MAPK/ NF-κB signaling and that targeting for these signaling may provide therapeutic opportunities in preventing metastasis mediated by Shh. Citation Format: Myoung Hee Kang, Bo Ram Kim, Joo Sung Park, Jung Guk Jeon, Hyun Sook An, You Jin Jang, Sun Il Kim, Jun Suk Kim, Sang Cheul Oh. Sonic hedgehog in gastric cancer metastasis; MAP Kinase/NFκB-dependent signaling pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2013-2814