Abstract
Barrett's metaplasia (BM) is an early lesion in the progression from oesophageal inflammation through dysplasia to the development of Barrett's adenocarcinoma (BA). Previous work indicates that BM and BA are associated with reduced E-cadherin expression and increased cytoplasmic/nuclear pools of its associated protein β-catenin. β-catenin participates in Wnt signalling and activates oncogene transcription by complexing with T-cells factors (TCF). One such oncogene is c-myc. We have previously shown that TNF-α can down-regulate E-cadherin expression. Here, we assess TNF-α expression in Barrett's metaplasia and examine if TNF-α can promote β-catenin mediated transcription of oncogenes in a gastrointestinal model system. Employing immunohistochemistry and Western blot analysis of oesophageal tissue, epithelial expression of TNF-α increases with progression along the metaplasia–dysplasia–carcinoma sequence (P<0.001). β-catenin mediated transcription was then assessed in TNF-α stimulated cell lines using the TOPFLASH reporter system whilst c-myc expression was assessed by real time PCR. In a columnar intestinal cell model, TNF-α induces c-myc expression which is induced via β-catenin mediated transcription (P<0.05). This β-catenin mediated transcription is independent of NF-κB activation. Thus, TNF-α is up-regulated in the progression of Barrett's oesophagus and β-catenin mediated transcription of c-myc is a novel pathway whereby elevated levels of TNF-α may lead to oncogene transcription and altered biology in gastrointestinal epithelia and metaplasia.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bailey T, Biddlestone L, Shepherd N, Barr H, Warner P, Jankowski J . 1998 Am. J. Pathol. 152: 135–144
Balkwill F, Mantovani A . 2001 Lancet 357: 539–545
Ben-Ze'ev A, Geiger B . 1998 Curr. Opin. Cell Biol. 10: 629–639
Birchmeier W, Behrens J . 1994 Biochim. Biophys. Acta. 1198: 11–26
Cameron AJ, Zinsmeister AR, Ballard DJ, Carney JA . 1991 Gastroenterology 99: 918–922
Cottam D, Rees R . 1993 Intl. J. Oncol. 2: 861–872
Dang CV, Resar LM, Emison E, Kim S, Li Q, Prescott JE, Wonsey D, Zeller K . 1999 Exp. Cell Res. 253: 63–77
Dixon MF, Neville PM, Mapstone NP, Moayyedi P, Axon AT . 2001 Gut 49: 359–363
Eliopoulos AG, Stack M, Dawson CW, Kaye KM, Hodgkin L, Sihota S, Rowe M, Young LS . 1997 Oncogene 14: 2899–2916
El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni Jr JF, Rabkin CS . 2000 Nature 404: 398–402
Eger A, Stockinger A, Schaffhauser B, Beug H, Foisner R . 2000 J. Cell Biol. 148: 173–187
Frommel T, Zarling E . 1999 Med. Hypotheses 52: 27–30
Goldblum JR, Vicari JJ, Falk GW, Rice TW, Peek RM, Easley K, Richter JE . 1998 Gastroenterology 114: 633–639
Haller D, Bode C, Hammes WP, Pfeifer AM, Schiffrin EJ, Blum S . 2000 Gut 47: 79–87
Hoschuetzky H, Aberle H, Kemler R . 1994 J. Cell Biol. 127: 1375–1380
Jankowski JAZ, Harrison RF, Perry I, Balkwill F, Tselepis C . 2000 Lancet 356: 2079–2085
Jankowski JAZ, Provenzale D, Moayyedi P . 2002 Gastroenterology 122: 588–590
Ji L, Arcinas M, Boxer L . 1994 Mol. Cell. Biol. 14: 7967–7974
Kemler R . 1993 Trends Genet. 9: 317–321
Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M, Bodmer WF, Moyer MP, Riecken EO, Buhr HJ, Hanski C . 1999 Proc. Natl. Acad. Sci. USA 96: 1603–1608
Menke-Pluymers MB, Schoute NW, Mulder AH, Hop WC, van Blankenstein M, Tilanus HW . 1992 Gut 33: 1454–1458
Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M, Kollias G, Balkwill F . 1999 Nat. Med. 5: 828–831
Murthy S, Mathur S, Field F . 2000 J. Biol. Chem. 275: 9222–9229
Nathke I . 1999 Mol. Pathol. 52: 166–173
Nishihira T, Hashimoto Y, Katayama M, Mori S, Kuroki TJ . 1993 J. Cancer Res. Clin. Oncol. 119: 441–449
Papadakis K, Taragan S . 2000 Gastroenterology 119: 1148–1157
Perry I, Tselepis C, Hoyland J, Iqbal TH, Scott D, Sanders SA, Cooper BT, Jankowski JA . 1999 Lab. Invest. 79: 1489–1499
Polakis P . 1999 Curr. Opin. Genet. Dev. 9: 15–21
Rockett JC, Larkin K, Darnton SJ, Morris AG, Matthews HR . 1997 Br. J. Cancer 75: 258–263
Sampliner R . 1998 Am. J. Gastroenterol. 93: 1028–1032
Schmitz H, Fromm M, Bentzel CJ, Scholz P, Detjen K, Mankertz J, Bode H, Epple HJ, Riecken EO, Schulzke JD . 1999 J. Cell Sci. 112: 137–146
Tetsu O, McCormick F . 1999 Nature 398: 422–426
Thomas P, Doddoli C, Lienne P, Morati N, Thirion X, Garbe L, Giudicelli R, Fuentes P . 1997 Br. J. Surg. 84: 110–125
van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H . 1997 Cell 88: 789–799
Acknowledgements
We would like to acknowledge Dr Rupert Ransford, Emma Brayson and Debbie Wakelin for help with the immunohistochemistry and cell culture and Dr Qu Luong for assistance with the real time PCR. We would also like to thank Dr Clive Morris, Dr Sabine Tejpar and Professor Lawrence Young for helpful comments during the preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tselepis, C., Perry, I., Dawson, C. et al. Tumour necrosis factor-α in Barrett's oesophagus: a potential novel mechanism of action. Oncogene 21, 6071–6081 (2002). https://doi.org/10.1038/sj.onc.1205731
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205731
Keywords
This article is cited by
-
Macrophage numbers in the marginal area of sarcomas predict clinical prognosis
Scientific Reports (2023)
-
Therapeutic Effect of Polaprezinc on Reflux Esophagitis in the Rat Model
Digestive Diseases and Sciences (2023)
-
Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival
Cancer Immunology, Immunotherapy (2020)
-
In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett’s sequence
BMC Gastroenterology (2019)
-
Predictive Biomarkers of Gastroesophageal Reflux Disease and Barrett’s Esophagus in World Trade Center Exposed Firefighters: a 15 Year Longitudinal Study
Scientific Reports (2018)