Abstract
BackgroundIL-1β is a pleiotropic pro-inflammatory cytokine and its up-regulation is closely associated with various cancers including gastrointestinal tumors. However, it remains unclear how IL-1β may contribute to the initiation and development of these inflammation-associated cancers. Here we investigated the role of IL-1β in colon cancer stem cell (CSC) development.MethodsUsing self-renewal assay, soft-agar assay, invasion assay, real-time PCR analysis, immunoblot assay and shRNA knockdown, we determined the effects of IL-1β on cancer stem cell development and epithelial-mesenchymal transition (EMT) in human primary colon cancer cells and colon cancer cell line HCT-116.ResultsWe found that IL-1β can increase sphere-forming capability of colon cancer cells in serum-free medium. IL-1β-induced spheres displayed an up-regulation of stemness factor genes (Bmi1 and Nestin) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activator Zeb1 was increased in IL-1β-induced spheres, indicating that there might be a close association between EMT and IL-1β-induced CSC self-renewal. Indeed, IL-1β treatment led to EMT of colon cancer cells with loss of E-cadherin, up-regulation of Zeb1, and gain of the mesenchymal phenotype. Furthermore, shRNA-mediated knockdown of Zeb1 in HCT-116 cells reversed IL-1β-induced EMT and stem cell formation.ConclusionOur findings indicate that IL-1β may promote colon tumor growth and invasion through activation of CSC self-renewal and EMT, and Zeb1 plays a critical role in these two processes. Thus, IL-1β and Zeb1 might be new therapeutic targets against colon cancer stem cells.
Highlights
IL-1β is a pleiotropic pro-inflammatory cytokine and its up-regulation is closely associated with various cancers including gastrointestinal tumors
Characterization of human primary colon cancer cells During the first week of culture, all cells freshly isolated from normal mucosa failed to survive, and the majority of cells isolated from colon tumor sections died as well, leaving only a few remaining healthy cells
To assess whether IL-1β-induced formation of cancer stem cell (CSC) was associated with epithelial-mesenchymal transition (EMT), we examined the expression of EMT activators using real-time PCR and western blot analyses
Summary
IL-1β is a pleiotropic pro-inflammatory cytokine and its up-regulation is closely associated with various cancers including gastrointestinal tumors. It remains unclear how IL-1β may contribute to the initiation and development of these inflammation-associated cancers. We investigated the role of IL-1β in colon cancer stem cell (CSC) development. Inflammatory cells and mediators are present in every tumor, including those that are not developed from chronic inflammation [1,2]. Interleukin-1β (IL-1β) is an important mediator of cancerrelated inflammation and can be secreted by immune, stromal and tumor cells [4]. Elevated IL-1β levels have been associated with increased colon tumor growth and invasion [9,10]. How IL-1β may contribute to the development of cancer has not been fully explored
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