Identification of novel interactions between AGR2 and ER chaperones in Barrett’s oesophagus and oesophageal adenocarcinoma
Exposure of the oesophagus to repeated gastric reflux can induce a metaplasia and dysplasia of the oesophageal epithelium, giving
rise to tissue more resembling the lining of the intestine. This condition is known as Barrett’s oesophagus and is widely considered a
premalignant condition leading to oesophageal adenocarcinoma. There is a high chance (estimated between 0.5-2% per year)
patients with Barrett’s will develop oesophageal adenocarcinoma  and patients with Barrett’s oesophagus are estimated to have a
30-fold higher chance of developing oesophageal adenocarcinoma when compared to the general population .
In Barrett’s oesophagus, and the glandular adenocarcinoma that follows, mucous production is switched on, acting as a defence
mechanism against the gastric content. The core components of mucous are the mucins, large glycoproteins that give mucous its
viscoelastic properties. It has previously been shown that the small 19 kDa protein disulphide isomerase (PDI) family member
anterior gradient-2 (AGR2) is essential for the synthesis and secretion of mucins. Multiple mucin isoforms, including intestinal MUC2
and the airway mucins MUC5AC and MUC5B have all been shown to interact with AGR2 and require it for proper function [1,2].
Mucins contain high numbers of cysteine residues that form intra and interchain disulphide bonds which give mucus its viscosity and
AGR2 is required for the correct synthesis of these disulphide bonds, although the exact mechanism of this function is unknown.
Previous studies in our laboratory have assessed the role of ER oxidoreductases in gastro-intestinal disease . Here, we have
exploited the solitary cysteine residue in the AGR2 protein to identify the unperturbed, steady state interactions of a PDI family