IL-1[beta] promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

Background IL-1[beta] 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-1[beta] may contribute to the initiation and development of these inflammation-associated cancers. H...

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Bibliographic Details
Published in:Molecular cancer 2012-11, Vol.11
Main Authors: Li, Yijing, Wang, Lei, Pappan, Loretta, Galliher-Beckley, Amy, Shi, Jishu
Format: Article
Language:English
Subjects:
Analysis
Biotechnology industry
Cancer cells
Colon
Colon cancer
Colorectal cancer
Development and progression
Drug resistance
Gastrointestinal diseases
Inflammation
Interleukins
Medical research
Proteins
Stem cells
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Summary:Background IL-1[beta] 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-1[beta] may contribute to the initiation and development of these inflammation-associated cancers. Here we investigated the role of IL-1[beta] in colon cancer stem cell (CSC) development. Methods Using self-renewal assay, soft-agar assay, invasion assay, real-time PCR analysis, immunoblot assay and shRNA knockdown, we determined the effects of IL-1[beta] on cancer stem cell development and epithelial-mesenchymal transition (EMT) in human primary colon cancer cells and colon cancer cell line HCT-116. Results We found that IL-1[beta] can increase sphere-forming capability of colon cancer cells in serum-free medium. IL-1[beta]-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-1[beta]-induced spheres, indicating that there might be a close association between EMT and IL-1[beta]-induced CSC self-renewal. Indeed, IL-1[beta] 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-1[beta]-induced EMT and stem cell formation. Conclusion Our findings indicate that IL-1[beta] 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-1[beta] and Zeb1 might be new therapeutic targets against colon cancer stem cells. Keywords: Colon cancer, Tumor microenvironment, Inflammation, Interleukin-1[beta], Cancer stem cells, Epithelial-mesenchymal transition, Zeb1
ISSN:1476-4598
1476-4598
DOI:10.1186/1476-4598-11-87