Role of nuclear factor kappa B and reactive oxygen species in the tumor necrosis factor-a-induced epithelial-mesenchymal transition of MCF-7 cells

Abstract

The microenvironment of the tumor plays an important role in facilitating cancer progression and activating dormant cancer cells. Most tumors are infiltrated with inflammatory cells which secrete cytokines such as tumor necrosis factor-α (TNF-α). To evaluate the role of TNF-α in the development of cancer we studied its effects on cell migration with a migration assay. The migrating cell number in TNF-α-treated group is about 2-fold of that of the control group. Accordingly, the expression of E-cadherin was decreased and the expression of vimentin was increased upon TNF-α treatment. These results showed that TNF-α can promote epithelial-mesenchymal transition (EMT) of MCF-7 cells. Further, we found that the expression of Snail, an important transcription factor in EMT, was increased in this process, which is inhibited by the nuclear factor kappa B (NFκB) inhibitor aspirin while not affected by the reactive oxygen species (ROS) scavenger N-acetyl cysteine. Consistently, specific inhibition of NFκB by the mutant IκBα also blocked the TNF-α-induced upregulation of Snail promoter activity. Thus, the activation of NFκB, which causes an increase in the expression of the transcription factor Snail is essential in the TNF-α-induced EMT. ROS caused by TNF-α seemed to play a minor role in the TNF-α-induced EMT of MCF-7 cells, though ROS per se can promote EMT. These findings suggest that different mechanisms might be responsible for TNF-α-and ROSinduced EMT, indicating the need for different strategies for the prevention of tumor metastasis induced by different stimuli. Correspondence

Metformin alleviated EMT and fibrosis after renal ischemia–reperfusion injury in rats

“…17 TNF-a could directly stimulate TGF-b1 production, collagen deposition in the renal cortex, increased interstitial volume, and deteriorating renal fibrosis, 18,19 TNF-a might also play an important role in EMT, perhaps by modulating TGF-b1 activity. 20,21 In our study, continuous administration of metformin successfully reduced the expression of TNF-a and IL-6, but transient administration of metformin did not. Renal fibrosis was characterized by excessive accumulation of ECM proteins, including increased expression of a-SMA, Vimentin, and loss of E-cadherin.…”

Reactive Oxygen Species and Tumor Metastasis

“…Recent studies have suggested the role of ROS in the induction of EMT in cancer cells. ROS can activate Snail and lead to EMT (Cannito et al, 2008;Dong et al, 2007) (Fig. 1).…”

Tumor and its microenvironment: A synergistic interplay

“…Due to the activation of Nitric Oxide Synthase 2 (NOX2), CAMs can directly produce ROS resulting in CAFs recruitment and MMPs activation [43]. Moreover, by secreting the master pro-inflammatory cytokine TNF␣, CAMs prime the NF-kB activation in both stromal and cancer cells, which in turn up-regulates SNAI1 expression [44]. In response to intrinsic and extrinsic oxidative stress, CAFs support tumor growth and promote EMT changes in cancer cells by secreting growth factors and ECM degrading proteases.…”