Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor.
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.
Guo
Yan-Shi
YS
Departments of Surgery and Ophthalmology, University of Texas Medical Branch, Galveston 77555, USA. yguo@utmb.edu
Cheng
Ji-Zhong
JZ
Jin
Gui-Fang
GF
Gutkind
J Silvio
JS
Hellmich
Mark R
MR
Townsend
Courtney M
CM
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology; D066246:ErbB Receptors / Q000235:genetics*; D005755:Gastrins / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*
D005755:Gastrins; D007527:Isoenzymes; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D014157:Transcription Factors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D066246:ErbB Receptors; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone