Abstract LB-199: ZEB factors link IL-1β-induced EMT and stem cell phenotypes in colon cancer

Abstract

Abstract Up-regulation of inflammatory cytokines such as IL-1β in tumor microenvironment has been associated with progression of human colorectal cancer. However, the exact molecular mechanisms by which inflammatory cytokines promote colon tumor growth are still unclear. Cancer stem cells (CSCs), a distinct subpopulation with self-renewal ability, drug resistance and high oncogenic potential, are thought to be responsible for tumor initiation and progression. Epithelia-mesenchymal transition (EMT), characterized by the repression of E-cardherin expression and increased cell mobility, is associated with enhanced metastasis. The objective of this study is to determine whether IL-1β may promote cancer progression by inducing EMT and colon CSC development. Here, we showed that IL-1β promoted E-cadherin repression in both human colon cancer cell line HCT-116 cells and primary colon cancer cells. Expression of E-cadherin transcription repressors ZEB1 and ZEB2 was up-regulated in IL-1β-treated HCT-116 and primary colon cancer cells, respectively. In addition, IL-1β-treated HCT-116 cells exhibited higher cell migratory ability. Moreover, IL-1β induced the expression of stem-cell marker Bmi-1 in both HCT-116 cells and primary colon cancer cells. IL-1β increased these cells’ ability of sphere formation in serum-free conditions and chemo-resistance; properties associated with colon CSCs. Taken together, these results indicate that IL-1β can induce EMT and promote generation of colon CSCs. More importantly, we found that ZEB1 and ZEB2, but not other E-cadherin transcriptional repressors (such as Snail and Twist), were consistently up-regulated in HCT-116 cells and primary colon cancer cells, respectively, during both processes of IL-1β-induced EMT and sphere formation. This suggests that ZEB factors may mediate IL-1β-induced EMT and generation of colon CSCs. Currently, this hypothesis is under evaluation using shRNAs to knock down ZEB1 in HCT-116 cells. Understanding the role of ZEB factors in IL-1β-mediated EMT and CSC development may lead to the identification of novel molecular targets for colon cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-199. doi:1538-7445.AM2012-LB-199