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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

Lookup NU author(s): Dr Lee Borthwick, Dr Aaron Ions GardnerORCiD, Professor Anthony De SoyzaORCiD, Professor Derek Mann, Professor Andrew FisherORCiD

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Abstract

Epithelial to mesenchymal transition (EMT) is a 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-beta1 (TGF-beta1) continues to be regarded as the key growth factor involved in driving EMT however recently tumour necrosis factor alpha (TNFalpha) has been demonstrated to accentuate TGF-beta1 driven EMT. In this study we investigate how various signalling pathways contribute to this accentuated effect. A549 cells were treated with TGF-beta1 (10ng/ml), TNFalpha (20ng/ml) or a combination of both for 72h and EMT assessed. The effect of selective inhibition of the SMAD, MAPK and NF-kappaB pathways on EMT was assessed. A549 cells treated with TGF-beta1 downregulate the expression of epithelial markers, increase the expression of mesenchymal markers, secrete matrix-metalloproteinases and become invasive. Significantly, TGF-beta1 driven EMT is accentuated by co-treatment with TNFalpha. SMAD 3 inhibition attenuated TGF-beta1 driven EMT but has no effect on the accentuation effect of TNFalpha. However, inhibiting IKKbeta blocked both TGF-beta1 driven EMT and the accentuating action of TNFalpha. Inhibiting p38 and ERK signalling had no effect on EMT. TNFalpha accentuates TGF-beta1 driven EMT in A549 cells via a SMAD 2/3 independent mechanism involving the NF-kappaB pathway independent of p38 and ERK 1/2 activation.

Publication metadata

Author(s): Borthwick LA, Gardner A, De-Soyza A, Mann DA, Fisher AJ

Publication type: Article

Publication status: Published

Journal: Cancer Microenvironment

Year: 2012

Volume: 5

Issue: 1

Pages: 45-57

Print publication date: 01/04/2012

Online publication date: 27/07/2011

Acceptance date: 18/07/2011

ISSN (print): 1875-2292

ISSN (electronic): 1875-2284

Publisher: Springer

URL: http://dx.doi.org/10.1007/s12307-011-0080-9

DOI: 10.1007/s12307-011-0080-9

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