Abstract 556: Cot/Tpl2 is required for neoplastic cell transformation induced by interleukin-22: a possible mechanism in breast carcinogenesis.

Abstract

Abstract Interleukin 22 (IL-22), a member of the IL-10 family of cytokines, is secreted T helper 17 (Th17) cells. Although IL-22 was recently reported to be a novel inflammation mediator through STAT3 signaling activation, the precise mechanisms of IL-22 in neoplastic cellular transformation and breast carcinogenesis are not well explored yet. Here, we report that IL-22 induced neoplastic transformation of JB6 Cl41 cells through activation of Cot/Tpl2. IL-22 dose- and time-dependently increased Cot/Tpl2 phosphorylation in JB6 Cl41 cells through IL-22 receptor. IL-22 phosphorylated MEK1/2, JNK1/2 and STAT3, which were inhibited by a specific inhibitor of Cot/Tpl2 kinase. When small interfering RNA (siRNA) of IL-22 and IL-22 receptor (IL-22R) were transfected into JB6 Cl41 cells, IL-22-induced Cot/Tpl2 phosphorylation was markedly decreased, followed by inhibition of MEK-ERK, JNK-c-Jun and STAT3 signaling pathway. Also, IL-22 activated c-fos and c-jun promoter activity, leading to increased activator protein-1 (AP-1) activity, which was suppressed by Cot/Tpl2 inhibitor. The in vivo chorioallantoic membrane (CAM) assay also showed that IL-22 increased tumor growth of JB6 Cl41 cells, whereas Cot/Tpl2 inhibitor suppressed the tumorigenesis induced by IL-22. In addition, knockdown of IL-22 and/or inhibition of Cot/Tpl2 diminished tumorigenecity of human breast cancer SKBR3 cells. Consistent with these observations, immunohistochemical staining showed that both expressions of IL-22 and Cot/Tpl2 proteins were highly upregulated in human breast cancers. Thus, this suggests that Cot/Tpl2 plays a pivotal role in IL-22-induced neoplastic cell transformation, and that Cot/Tpl2 may be the therapeutic target of breast cancer promoted by IL-22. Citation Format: Karam Kim, Hong Seok Choi. Cot/Tpl2 is required for neoplastic cell transformation induced by interleukin-22: a possible mechanism in breast carcinogenesis. [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 556. doi:10.1158/1538-7445.AM2013-556 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.