Received September 12, 2007
Revised October 4, 2007
Accepted after revision October 9, 2007

¹ University of Liverpool

^* To whom correspondence should be addressed. E-mail: r.dimaline{at}liv.ac.uk.

	Abstract

The CCK2 receptor mediates the physiological functions of gastrin in the stomach including stimulation of acid secretion and cellular proliferation and migration, but little is known about the factors that regulate its expression. We identified endogenous CCK2R expression in several cell lines and used luciferase promoter-reporter constructs to define the minimal promoter required for transcription in human gastric adenocarcinoma, AGS, and rat gastric mucosa, RGM1, cells. Consensus binding sites for SP1, C/EBP and GATA were essential for activity. Following serum withdrawal from RGM1 and AR42J cells, endogenous CCK2R mRNA abundance and activity of a CCK2R promoter-reporter construct were significantly elevated. CCK2R transcription was also increased on AGS-GR and RGM1 cells by gastrin through mechanisms partly dependent upon PKC and MEK. Gastrin significantly increased endogenous CCK2R expression in RGM1 cells and CCK2R protein expression was elevated in the stomach of hypergastrinaemic animals. In mice with cryoulcers in the acid secreting mucosa, CCK2R expression increased progressively in the regenerating mucosa adjacent to the ulcer repair margin, evident at six days post injury and maximal at 13 days. De novo expression of CCK2R was observed in the submucosa beneath the repairing ulcer crater 6-9 days post injury. Many of the cells in mucosa and submucosa that expressed CCK2R in response to cryoinjury were identified as myofibroblasts since they co-expressed vimentin and smooth muscle -actin but not desmin. The data suggest that increased CCK2R expression might influence the outcome of epithelial inflammation or injury and that the response may be mediated in part by myofibroblasts.

Key Words: Gastrin, Receptor, Stomach