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 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.