Abstract 2299: Identification of the extrinsic inflammatory factors and intrinsic signaling molecules that cooperate with Snail in mediating ovarian cancer metastasis
Authors: Jin Hongyan , Zhou Jiayi , Lu Yiling , Zhou Binhua P. , Yu Yinhua 
Published: February 2011

Abstract
Although peritoneal inflammation plays a causative role in ovarian tumor metastasis, extrinsic inflammatory factors and intrinsic molecules that involve in this process have not been well studied. Snail, a key epithelial-mesenchymal transition (EMT) inducer, has been shown to correlate with cancer metastasis. This molecule is highly unstable and has a short half-life. Recent studies suggested that stabilized Snail is required for inflammation-induced cell migration and invasion. In our studies, immunohistochemical analysis on ovarian cancer progression tissue array demonstrated that the expression of Snail was significantly higher in metastatic lesions, and Snail expression correlated with the stage of ovarian cancer. When expression of Snail was knocked down, the size of primary ovarian tumor and the numbers of metastatic lesions were significantly reduced, indicating that Snail plays an important role in ovarian cancer metastasis. To understand the role of extrinsic inflammatory factors that may induce Snail and speed ovarian cancer metastasis, we have established a Tet-on inducible Snail-SKOv3 cell line. Migration and invasion were greatly increased when Snail was induced. Interestingly, TNFα, TGFβ1, PMA and IL-6 could increase the expression of Snail in a dose and time dependent fashion and the increased Snail level correlated with the enhancement of cell migration in this cell line. In addition, these inflammatory factors could also increase endogenous Snail expression in HO8910-PM ovarian cancer cell line. Consistent with these observations, phospho-GSK3β was up-regulated, and expression of THBS1, E-cadherin, deltaEF-1 and TIMP3 were down-regulated in Snail-SKOv3 cells when Snail was induced. Our data indicate that TNFα, TGFβ1, PMA and IL-6 constitute the critical extrinsic inflammatory factors for induction of Snail in mediating ovarian cancer metastasis. To further identify the intrinsic molecules that may cooperate Snail in facilitating metastasis, we performed Reverse Phase Protein Arrays (RPPA) and Western blotting analysis. We found that S6pS240, one of the effectors related to proliferation and apoptosis/autophagy, was significantly upregulated in Snail-SKOv3 cells when Snail was induced. Moreover, several other signaling molecules, such as DNMT1, AMPK-pT172, AMPKα, p70S6K, SMAD3, TCH1, HSP70, ETV6, and COX2, were also found up-regulated or down-regulated by Snail induction. Our results suggest that these intrinsic signaling molecules may form a complex signaling network to cooperate with Snail. Taken together, we have identified the extrinsic inflammatory factors and intrinsic signaling molecules that either induce or cooperate with Snail in mediating ovarian cancer metastasis. Our study provides new therapeutic targets for innovative approach for preventing and treating metastatic ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2299.