Abstract 1422: Interleukin-17A activates tumor progression locus 2 to induce neoplastic cell transformation and breast carcinogenesis.

Abstract

Abstract Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated CD4+ memory T cells. Although the role of T cells in cancer promotion has been examined, little is known about the underlying molecular mechanisms of interleukin-17 A (IL-17A) in carcinogenesis. In the present study, we first found that IL-17A induces neoplastic transformation of JB6 Cl41 cells through activation of tumor progression locus 2 (TPL2). IL-17A activates MEKs-ERKs, JNKs-c-Jun, and STAT3 signaling pathways, which are inhibited by a TPL2 kinase inhibitor (TKI). Furthermore, IL-17A activates c-fos and c-jun promoter activity, resulting in increased activator protein-1 (AP-1) activity. When small interfering RNA (siRNA) of IL-17A receptor (IL-17R), IL-17A, and TPL2 were introduced into JB6 Cl41 cells, respectively, IL-17A-induced AP-1 activity was significantly decreased compared to control cells. Similarly, TPL2 inhibition suppressed AP-1 activity induced by IL-17A. The knockdown of IL-17R and TKI treatment in JB6 Cl41 cells resulted in decreased IL-17A-induced cell transformation. The in vivo chorioallantoic membrane (CAM) assay also showed that IL-17A increased tumor formation of JB6 Cl41 cells, whereas TKI inhibited the tumorigenesis promoted by IL-17A. Consistent with these observations, knockdown of IL-17A and/or inhibition of TPL2 attenuated tumorigenecity of human breast cancer MCF7 cells. Moreover, immunohistochemical staining showed that both expressions of IL-17A and TPL2 were highly upregulated in human breast cancers. Together, our findings point to a critical role for the IL-17A-induced TPL2 signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may therefore effectively inhibit carcinogenesis. Citation Format: Garam Kim, Hong Seok Choi. Interleukin-17A activates tumor progression locus 2 to induce neoplastic cell transformation and 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 1422. doi:10.1158/1538-7445.AM2013-1422 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.