Tumour necrosis factor-α in Barrett's oesophagus: a potential novel mechanism of action

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 beta-catenin. beta-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-alpha can down-regulate E-cadherin expression. Here, we assess TNF-alpha expression in Barrett's metaplasia and examine if TNF-alpha can promote beta-catenin mediated transcription of oncogenes in a gastrointestinal model system. Employing immunohistochemistry and Western blot analysis of oesophageal tissue, epithelial expression of TNF-alpha increases with progression along the metaplasia-dysplasia-carcinoma sequence (P<0.001). beta-catenin mediated transcription was then assessed in TNF-alpha 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-alpha induces c-myc expression which is induced via beta-catenin mediated transcription (P<0.05). This beta-catenin mediated transcription is independent of NF-kappaB activation. Thus, TNF-alpha is up-regulated in the progression of Barrett's oesophagus and beta-catenin mediated transcription of c-myc is a novel pathway whereby elevated levels of TNF-alpha may lead to oncogene transcription and altered biology in gastrointestinal epithelia and metaplasia.