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

Overview

Journal Cancer Microenviron

Publisher Springer

Specialty Oncology

Date 2011 Jul 28

PMID 21792635

Citations 34

Authors

Lee A Borthwick

Aaron Gardner

Anthony De Soyza

Derek A Mann

Andrew J Fisher

Affiliations

Soon will be listed here.

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-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 TGF-β1 driven EMT but has no effect on the accentuation 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.

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References

Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A . Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J. 1999; 14(5):1015-22. DOI: 10.1183/09031936.99.14510159. View

Kuno K, Sukegawa K, Ishikawa Y, Orii T, Matsushima K . Acid sphingomyelinase is not essential for the IL-1 and tumor necrosis factor receptor signaling pathway leading to NFkB activation. Int Immunol. 1994; 6(8):1269-72. DOI: 10.1093/intimm/6.8.1269. View

El-Gamel A, Sim E, Hasleton P, Hutchinson J, Yonan N, Egan J . Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation. J Heart Lung Transplant. 1999; 18(9):828-37. DOI: 10.1016/s1053-2498(99)00047-9. View

Chuang M, Sun K, Tang S, Deng M, Wu Y, Sung J . Tumor-derived tumor necrosis factor-alpha promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells. Cancer Sci. 2008; 99(5):905-13. PMC: 11158824. DOI: 10.1111/j.1349-7006.2008.00756.x. View

Bates R, Mercurio A . Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 2003; 14(5):1790-800. PMC: 165077. DOI: 10.1091/mbc.e02-09-0583. View

Solis-Herruzo J, Brenner D, Chojkier M . Tumor necrosis factor alpha inhibits collagen gene transcription and collagen synthesis in cultured human fibroblasts. J Biol Chem. 1988; 263(12):5841-5. View

Lin C, Lin C, Chen K, Wu J, Huang S, Wang S . Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction. FEBS Lett. 2006; 580(13):3042-50. DOI: 10.1016/j.febslet.2006.04.049. View

Liu X . Inflammatory cytokines augments TGF-beta1-induced epithelial-mesenchymal transition in A549 cells by up-regulating TbetaR-I. Cell Motil Cytoskeleton. 2008; 65(12):935-44. DOI: 10.1002/cm.20315. View

Brandl M, Seidler B, Haller F, Adamski J, Schmid R, Saur D . IKK(α) controls canonical TGF(ß)-SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in panc1 cells. J Cell Sci. 2010; 123(Pt 24):4231-9. DOI: 10.1242/jcs.071100. View

10.

Ear T, Fortin C, Simard F, McDonald P . Constitutive association of TGF-beta-activated kinase 1 with the IkappaB kinase complex in the nucleus and cytoplasm of human neutrophils and its impact on downstream processes. J Immunol. 2010; 184(7):3897-906. DOI: 10.4049/jimmunol.0902958. View

11.

Derynck R, Zhang Y . Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003; 425(6958):577-84. DOI: 10.1038/nature02006. View

12.

Ziegenhagen M, Schrum S, Zissel G, Zipfel P, Schlaak M, Muller-Quernheim J . Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis. J Investig Med. 1998; 46(5):223-31. View

13.

Kelly M, Kolb M, Bonniaud P, Gauldie J . Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des. 2003; 9(1):39-49. DOI: 10.2174/1381612033392341. View

14.

Huber M, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H . NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004; 114(4):569-81. PMC: 503772. DOI: 10.1172/JCI21358. View

15.

Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G . The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol. 2001; 80(8):554-61. DOI: 10.1078/0171-9335-00182. View

16.

Javelaud D, Mauviel A . Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene. 2005; 24(37):5742-50. DOI: 10.1038/sj.onc.1208928. View

17.

Jain R, Shaul P, Borok Z, Willis B . Endothelin-1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-beta1. Am J Respir Cell Mol Biol. 2007; 37(1):38-47. PMC: 1899351. DOI: 10.1165/rcmb.2006-0353OC. View

18.

Kasai H, Allen J, Mason R, Kamimura T, Zhang Z . TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005; 6:56. PMC: 1177991. DOI: 10.1186/1465-9921-6-56. View

19.

Luo Y, Zhou H, Krueger J, Kaplan C, Lee S, Dolman C . Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest. 2006; 116(8):2132-2141. PMC: 1513049. DOI: 10.1172/JCI27648. View

20.

Regan M, Kirk S, Hurson M, Sodeyama M, Wasserkrug H, Barbul A . Tumor necrosis factor-alpha inhibits in vivo collagen synthesis. Surgery. 1993; 113(2):173-7. View