Prostaglandin E2 stimulates progression-related gene expression in early colorectal adenoma cells

摘要

Upregulation of cyclooxygenase-2 (COX-2) and prostaglandin-dependent vascularisation in small adenomatous polyps is an essential part of colon carcinogenesis. To study the underlying cellular mechanisms, LT97 and Caco2 human colorectal tumour cells not expressing endogenous COX-2 were exposed to 1?μM prostaglandin E2 (PGE2) in their medium. At 30?min after addition, expression of c-fos was stimulated 5-fold and 1.3-fold, respectively, depending on the activation of both extracellular signal-regulated kinase and p38. The amount of c-jun in nuclear extracts was increased 20% in LT97 cells. Expression of COX-2 was upregulated 1.7-fold in LT97 cells and 1.5-fold in Caco2 2?h after prostaglandin (PG) addition by a p38-mediated pathway. The known PGE2 target gene vascular endothelial growth factor (VEGF) was not modulated. Effects of sustained PGE2 production were studied in VACO235 cells that have high endogenous COX-2 and in LT97 cells infected with an adenovirus expressing COX-2. Prostaglandin E2 secretion into the medium was 1–2?nM and 250?pM, respectively. Expression of both VEGF and c-fos was high in VACO235 cells. In LT97 cells, COX-2 upregulated c-fos expression and c-jun content in nuclear extracts 1.7- and 1.2-fold, respectively, in a PG-dependent way. This shows that exogenous PGE2 as well as COX-2 overexpression affect signalling and gene expression in a way that enhances tumour progression.