Abstract
Gastrin is a hormone produced by G-cells in the normal gastric antrum. However, colorectal carcinoma cells may aberrantly produce gastrin and exhibit increased expression of cholecystokinin B (CCK-B)/gastrin receptors. Gastrin is trophic for the normal gastric oxyntic mucosa and exerts a growth-promoting action on gastrointestinal malignancy. Thus, gastrin may act as an autocrine/paracrine or endocrine factor in the initiation and progression of colorectal carcinoma. The molecular mechanisms involved have not been elucidated. Hypergastrinemia induced by Helicobacter pylori infection is associated with increased cyclooxygenase-2 (COX-2) expression in gastric and colorectal tissues, suggesting the possibility that gastrin up-regulates COX-2 expression in these tissues; this has not been confirmed. We report here that gastrin significantly increases the expression of COX-2 mRNA and protein, the activity of the COX-2 promoter, and the release of prostaglandin E(2) from a rat intestinal epithelial cell line transfected with the CCK-B receptor. These actions were dependent upon the activation of multiple MAPK signal pathways, including ERK5 kinase; transactivation of the epidermal growth factor receptor; and the increased expression and activities of transcription factors ELK-1, activating transcription factor-2, c-Fos, c-Jun, activator protein-1, and myocyte enhancer factor-2. Thus, our findings identify the signaling pathways coupling the CCK-B receptor with up-regulation of COX-2 expression. This effect may contribute to this hormone-dependent gastrointestinal carcinogenesis, especially in the colon.
Highlights
From the Departments of ‡Surgery and ¶Ophthalmology, University of Texas Medical Branch, Galveston, Texas 77555 and the ʈOral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
We report here that gastrin significantly increases the expression of COX-2 mRNA and protein, the activity of the COX-2 promoter, and the release of prostaglandin E2 from a rat intestinal epithelial cell line transfected with the cholecystokinin B (CCK-B) receptor
The purpose of this study was to examine whether the activation of the cholecystokinin B receptor (CCK-BR) by gastrin leads to up-regulation of COX-2 expression in intestinal epithelial cells and, if so, to determine the signaling pathways signal transducer and activator of transcription; dn, dominant-negative; HB-EGF precursor to yield mature ligand (HB-EGF), heparin-binding epidermal growth factor-like growth factor
Summary
From the Departments of ‡Surgery and ¶Ophthalmology, University of Texas Medical Branch, Galveston, Texas 77555 and the ʈOral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892. Our findings identify the signaling pathways coupling the CCK-B receptor with up-regulation of COX-2 expression This effect may contribute to this hormone-dependent gastrointestinal carcinogenesis, especially in the colon. Watson et al [10, 11] showed that immune neutralization of gastrin or its cognate receptor by antisera inhibits the growth, invasion, and metastasis of colorectal tumors These findings suggest that gastrin plays a crucial role in colorectal cancer development; the molecular mechanisms have not been defined. Recent evidence shows that 85% of colorectal cancer patients have H. pylori infection and that these patients consistently overexpress COX-2 in the colonic cancer tissue, but not in normal mucosa, where only COX-1 is detected. The fact that H. pylori induced hypergastrinemia is associated with increased COX-2 expression in gastric and colonic tissues suggests that gastrin may regulate COX-2 expression, but this possibility has not been confirmed [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
