Figure 8 Proposed model of COX‐2 induction by unconjugated bile acids in oesophageal neoplasia. (A) Summary of effects (Western analysis) of unconjugated bile acids on signalling pathways in transformed oesophageal epithelial cells (SEG‐1). (B) Proposed model of pathways by which unconjugated bile acids induce COX‐2 expression based on current data. Unconjugated bile acids generate ROS production, which activate PI3K/AKT and ERK1/2 signalling pathways leading to AP‐1 and CREB dependent COX‐2 induction. The pharmacological inhibitors (LY294002 and U0126) and genetic approaches (DN AKT, DN Ap‐1 and CREB‐siRNA) used to dissect these pathways are depicted here. Previous data²³ and data from our laboratory (Supplemental fig 1) indicate that COX‐2 induction may be blocked by inhibitors of PKC. PKC plays a role in the bile‐acid‐induced generation of ROS in colonic epithelial cells (ie acts upstream of ROS), but the precise role of PKC in COX‐2‐induction in oesophageal epithelial cells remains to be elucidated. Crosstalk between PI3K and ERK1/2 is based on supplemental data not presented in the main manuscript but available as Supplemental fig 2.