Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Abstract

process by which an epithelial cell alters its phenotype to that of a mesenchymal cell and plays a critical role in embryonic development, tumour invasion and metastasis and tissue fibrosis. Transforming growth factor-β1 (TGF-β1) continues to be regarded as the key growth factor involved in driving EMT however recently tumour necrosis factor α (TNFα) has been demonstrated to accentuate TGF-β1 driven EMT. In this study we investigate how various signalling pathways contribute to this accentuated effect. A549 cells were treated with TGF-β1 (10 ng/ml), TNFα (20 ng/ml) or a combination of both for 72 h and EMT assessed. The effect of selective inhibition of the SMAD, MAPK and NF-κB pathways on EMT was assessed. A549 cells treated with TGF-β1 downregulate the expression of epithelial markers, increase the expression of mesenchymal markers, secrete matrix-metalloproteinases and become invasive. Significantly, TGF-β1 driven EMT is accentuated by co-treatment with TNFα. SMAD 3 inhibition attenuated effect of TNFα. However, inhibiting IKKβ blocked both TGF-β1 driven EMT and the accentuating action of TNFα. Inhibiting p38 and ERK signalling had no effect on EMT. TNFα accentuates TGF-β1 driven EMT in A549 cells via a SMAD 2/3 independent mechanism involving the NF-κB pathway independent of p38 and ERK 1/2 activation.

Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

“…This growth factor may be triggered by TNF-α, which is produced by tumour-infiltrating macrophages. The binding of TGFβ with TGFβR1 and/or TGFβR2 receptors triggers the phosphorylation of Smad2 and Smad3 dimers, which dissociate from the receptors to interact with Smad4; subsequently these dimers enter the nucleus to regulate EMT [63] . Additionally, the TGFβ-Smad pathway induces the high motility group A2 gene (HMGA2), which mediates EMT; HMGA2 is a nuclear factor that links TGFβ with the EMT-inducing transcription factors Twist and Snail1 and 2.…”

Inflammatory mediators, tumor necrosis factor-α and interferon-γ, induce EMT in human PTC cell lines

“…EMT was initially reported in embryonic development; however, it also occurs during tumor metastasis (14,15) and appears to be common in PTC invasion (16)(17)(18)(19). Transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) are inflammatory cytokines that are able to stimulate EMT in thyroid cancer cells or thyroid cells cultured ex vivo (20,21 of TNF-α and IFN-γ have been demonstrated to induce invasion and metastasis of cancer (11,12,(22)(23)(24) via mechanisms involving the SMAD, NF-κB, AKT/GSK-3β and JAK/STAT signaling pathways. Thus, EMT represents a convergence point between inflammation and the progression of cancer (25); however, the mechanisms through which inflammation is involved in the different stages of tumor invasion, intravasation and subsequent metastasis to the distant organ sites remain poorly defined (26).…”

BMP2 Induces PANC-1 cell invasion by MMP-2 overexpression through ROS and ERK

“…As a result, cells undergoing EMT gain mesenchymal cell-like functions including invasive potential and the ability to secrete extra cellular matrix (ECM) proteins and MMPs (34). Previous studies suggest that EMT is regulated by a number of growth factors such as TGF-β1, fibroblast growth factor, epithelial growth factor, and hepatocyte growth factor (35)(36)(37). Moreover, several BMPs, particularly BMP7 and BMP4, have been implicated in EMT in various organs such as the kidney and lung (38,39).…”