Abstract LB-326: Zeb1 regulates inflammation-induced invasion and self-renewal of colon cancer cells.

Abstract

Abstract Up-regulation of inflammatory cytokines such as IL-1β in tumor microenvironment has been associated with progression of human colorectal cancer, although the exact molecular mechanisms are still unclear. To understand how IL-1β influences colon cancer cell behaviors, we used a human colon cancer cell line HCT-116 as well as primary human colon cancer cells derived from a patient, which more closely reflect the properties of the primary tumor than established cell lines. Here, we demonstrate that IL-1β promotes epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) development in colon cancer. IL-1β treatment resulted in loss of E-cadherin and gain of a mesenchymal phenotype in both HCT-116 cells and primary colon cancer cells. Among E-cadherin suppressors, Zeb1 was up-regulated in IL-1β-induced EMT cells. Consistent with EMT properties, IL-1β-treated HCT-116 cells exhibited higher cell migratory ability. Moreover, IL-1β induced expression of stem-cell marker Bmi-1 in both HCT-116 cells and primary colon cancer cells. IL-1β increased these cells’ self-renewal ability to form spheres 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 CSCs in colon cancer. More importantly, we found that ZEB1, but not other E-cadherin transcriptional repressors (such as Zeb2, Snail and Twist), was consistently up-regulated in IL-1β-induced EMT cells and sphere cells. This suggests that Zeb1 links IL-1β-induced CSC self-renewal and EMT in colon cancer cells. Moreover, knockdown of Zeb1 in HCT-116 cells using shRNAs reversed the IL-1β effects on these two processes, further indicating that Zeb1 is essential for IL-1β-induced stem cell and EMT phenotypes in colon cancer cells. Our finding indicates that IL-1β promotes colon tumor growth and invasion through activation of CSC self-renewal and EMT, while Zeb1 plays a critical role in activation of these two processes. Thus, targeting tumor microenvironment cytokines or Zeb1 might form the basis of a promising treatment for colon cancer. Citation Format: Lei Wang, Yijing Li, Amy Beckley, Lorretta Pappan, Jishu Shi. Zeb1 regulates inflammation-induced invasion and self-renewal of colon cancer cells. [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 LB-326. doi:10.1158/1538-7445.AM2013-LB-326 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.