Epithelial–Mesenchymal Transition (EMT) Induced by TNF-α Requires AKT/GSK-3β-Mediated Stabilization of Snail in Colorectal Cancer

Hao Wang,Hong-Sheng Wang,Jun Du,Fan Zhang,Shao-Hui Cai,Bin-Hua Zhou,Xian-Feng Wang,Cui-Lin Li,Xian-Zhang Bu,Ge Zhang,Srikumar P Chellappan

doi:10.1371/journal.pone.0056664

Hao Wang, Hong-Sheng Wang + Show 9 more

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https://doi.org/10.1371/journal.pone.0056664

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Journal: PloS one	Publication Date: Feb 19, 2013
Citations: 249	License type: CC BY 4.0

Abstract

Chronic inflammation-promoted metastasis has been considered as a major challenge in cancer therapy. Pro-inflammatory cytokine TNFα can induce cancer invasion and metastasis associated with epithelial–mesenchymal transition (EMT). However, the underlying mechanisms are not entirely clear. In this study, we showed that TNFα induces EMT in human HCT116 cells and thereby promotes colorectal cancer (CRC) invasion and metastasis. TNFα-induced EMT was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin and fibronectin with a concomitant decrease of E-cadherin and Zona occludin-1(ZO-1). TNFα treatment also increased the expression of transcription factor Snail, but not Slug, ZEB1 and Twist. Overexpression of Snail induced a switch from E-cadherin to N-cadherin expression in HCT116 cells, which is a characteristic of EMT. Conversely, knockdown of Snail significantly attenuated TNFα-induced EMT in HCT116 cells, suggesting that Snail plays a crucial role in TNFα-induced EMT. Interestingly, exposure to TNFα rapidly increased Snail protein expression and Snail nuclear localization but not mRNA level upregulation. Finally, we demonstrated that TNFα elevated Snail stability by activating AKT pathway and subsequently repressing GSK-3β activity and decreasing the association of Snail with GSK-3β. Knockdown of GSK-3β further verified our finding. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of Snail is required for TNFα-induced EMT in CRC cells. Our study provides a better understanding of inflammation-induced CRC metastasis.

Highlights

Chronic inflammation has been identified to be intimately associated with tumorigenesis [1,2]
Tumor necrosis factor a (TNFa) Induces epithelial–mesenchymal transition (EMT) in HCT116 Cells The increased migration and invasion abilities of tumor cells are reminiscent of the events at EMT, during which, the epithelial makers E-cadhein and ZO-1 are down-regulated, whereas the mesenchymal markers N-cadherin and fibronectin are up-regulated [27]
A major challenge during cancer therapy is metastasis induced by chronic inflammation

Summary

Introduction

Chronic inflammation has been identified to be intimately associated with tumorigenesis [1,2]. Increasing evidences have proved that the inflammatory tumor microenvironment plays a crucial role in tumor development and metastasis [3]. Tumor microenvironment is largely orchestrated by inflammatory cells, which facilitate extracellular matrix breakdown, angiogenesis, and tissue remodeling, promote tumor cell motility [4]. Tumor cells themselves can secrete proinflammatory cytokines which contribute directly to malignant progression [5]. The complex interactions between the tumor and inflammatory cells mediated by inflammatory cytokines are an essential aspect of the tumor microenvironment [6]. Tumor necrosis factor a (TNFa), a proinflammatory cytokine predominantly produced by macrophages, is a key molecule regulating the inflammatory processes in tumor promotion. Mounting evidences suggested that TNFa mediates many critical processes of tumor progression, including oncogene activation, DNA damage, and tumor metastasis [7]

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