IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation

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.

Novel insights into Notum and glypicans regulation in colorectal cancer

“…The above observation is consistent with other data that report that the transgenic overexpression of IL1β in gastric mucosa is sufficient to induce gastric cancer in mice [35]. New findings have recently indicated that IL1β may promote colon tumor growth and invasion via the activation of cancer stem cell self-renewal and epithelial-mesenchymal transition (EMT) [36] As expected, the second most dysregulated canonical pathway in adenocarcinoma was the Wnt/β-catenin pathway. Wnt target genes are varied and context-specific [37] because Wnt/β-catenin signaling controls proliferation, cell fate determination and differentiation in numerous developmental stages and in adult tissue homeostasis.…”

ZEB1‐regulated inflammatory phenotype in breast cancer cells

“…IL‐1β promotes colon cancer cell stemness and invasiveness (Li et al ., 2012). IL‐8 is also associated with cancer stem cell‐like properties, and its expression correlates with poor prognosis in human pancreatic cancer (Chen et al ., 2014).…”

Asbestos-Induced Mesothelial to Fibroblastic Transition Is Modulated by the Inflammasome

“…IL-1b promotes EMT and cancer cell stemness in a number of cell types. 8,9 Cell typeespecific studies on the importance of the inflammasome for cancers with an inflammatory signature have indicated that the inflammasome is a key player in the etiology of these cancers.…”

“…7 In addition to promoting fibrosis, IL-1b induces epithelial to mesenchymal transition (EMT) in corneal endothelial cells and induces stemness in colon cancer cells through the activation of transcription factors that regulate the mesenchymal phenotype. 8,9 On the other hand, NLRP3 and apoptosis speck-like protein containing a CARD domain (ASC) (an adaptor protein for the assembly of the inflammasome) both play a role in transforming growth factor (TGF)-b signaling independent of their inflammasome activity in tubular epithelial cells. 10 We therefore hypothesized that the NLRP3 inflammasome and its products facilitate mesothelial to fibroblastic transition (MFT) of HMCs in response to asbestos exposure.…”