Stress and Redox-dependent Chaperone Interactions in the Endoplasmic Reticulum in Barrett's Oesophagus

Abstract

Barrett’s Oesophagus (BO) is an acquired condition which alters the normal structure of the distal oesophagus. BO is important as it is the only known precursor lesion for Oesophageal Adenocarcinoma (OAC) with an annual conversion rate of approximately 0.3%. There is a strong correlation between acid-reflux and the development of BO, with patients with BO having a high incidence of bile acids in their refluxate, bile acids have been implicated in ER stress and disruption of protein folding which may be important in the transition from BO to OAC.
Over-expression GPx7 has been shown to protect oesophageal cells from bile acid induced stress. However, there is evidence to suggest that GPx7 is down regulated by hypermethylation of its promoter in BO. Prdx4 also has an antioxidant role but has not been investigated fully in BO and OAC, Finally AGR2 is a member of the PDI family which has been implicated in a number of cancers and may play a role in the development of OAC.
This thesis did not find any noticeable expression of GPx7 in OE cells or in tissue samples of BO and OAC. Western blotting of OE cells showed a difference in redox poise between OE19 and OE33 cells and IHC showed expression of Prdx4 is gastric-like cells in BO but none in OAC tumour cells. AGR2 did not appear to be expressed in the normal oesophagus but was present in gastric-like secretory cells in BO which appeared to remain closely associated with tumour cells in OAC. Cellular experiments showed that AGR2 forms redox dependant interactions within OE cells. Taken together this may suggest a relationship between Prdx4 and AGR2 and the transition of BO to OAC.