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Purpose: Transcription factor SOX2 is expressed in normal gastric mucosae but not in the normal colon. We aimed to clarify the role of SOX2 with reference to pepsinogen expression in the gastrointestinal epithelium., Methods: We analyzed expression of SOX2 and pepsinogens, differentiation markers of the stomach, in ten gastric cancer (GC) and ten colorectal cancer (CRC) cell lines. The effects of over-expression and down-regulation of SOX2 on pepsinogen expression were also examined., Results: Six GC and five CRC cell lines showed SOX2 expression on RT-PCR. Expression of pepsinogen A was detectable in eight GC and seven CRC cell lines, whereas the majority of the cell lines expressed pepsinogen C. Over-expression of SOX2 up-regulated expression of pepsinogen A but not that of pepsinogen C in 293T human embryonic kidney cells, and some GC and CRC cell lines. Moreover, pepsinogen A expression was significantly reduced by SOX2 RNA interference in two GC cell lines., Conclusion: These data suggest that SOX2 plays an important role in regulation of pepsinogen A, and ectopic expression of SOX2 may be associated with abnormal differentiation of colorectal cancer cells.

Unlabelled: Ghrelin, a nature ligand for the growth hormone secretagogue receptor (GHS-R), stimulates a release of growth hormone, prolactin and adrenocorticotropic hormone. Also, ghrelin increases food intake in adult rats and humans and exhibits gastroprotective effect against experimental ulcers induced by ethanol or stress. The aim of present study was to examine the influence of ghrelin administration on gastric and duodenal growth and expression of pepsin and enterokinase in young mature rats with intact or removed pituitary., Methods: Two week after sham operation or hypophysectomy, eight week old Wistar male rats were treated with saline (control) or ghrelin (4, 8 or 16 nmol/kg/dose) i.p. twice a day for 4 days. Expression of pepsin in the stomach and enterokinase in the duodenum was evaluated by real-time PCR., Results: In animals with intact pituitary, treatment with ghrelin increased food intake, body weight gain and serum level of growth hormone and insulin-like growth factor-1 (IGF-1). These effects were accompanied with stimulation of gastric and duodenal growth. It was recognized as the significant increase in gastric and duodenal weight and mucosal DNA synthesis. In both organs, ghrelin administered at the dose of 8 nmol/kg caused maximal growth-promoting effect. In contrast to these growth-promoting effects, administration of ghrelin reduced expression of mRNA for pepsin in the stomach and was without effect on expression of mRNA for enterokinase in the duodenum. Hypophysectomy alone lowered serum concentration of growth hormone under the detection limit and reduced serum level of IGF-1 by 90%. These effects were associated with reduction in daily food intake, body weight gain and gastroduodenal growth. In hypophysectomized rats, administration of ghrelin was without significant effect on food intake, body weight gain or growth of gastroduodenal mucosa. Also, serum concentration of growth hormone or IGF-1 was not affected by ghrelin administration in rats with removed pituitary., Conclusion: Administration of ghrelin stimulates gastric and duodenal growth in young mature rats with intact pituitary, but inhibits expression of mRNA for pepsin in the stomach. Growth hormone and insulin-like growth factor-1 play an essential role in growth-promoting effects of ghrelin in the stomach and duodenum.

Chicken stomach provides an extremely useful experimental system for the analysis of molecular nature of the morphogenesis and cytodifferentiation of digestive organs in vertebrates. We identified several genes of which expression is important for the normal development of the stomach. Especially, bone morphogenetic protein-2 is necessary for the mesenchymal action in inducing gland formation in the epithelium of the stomach. Some transcription factors such as cSox2 and cGATA5 are involved in the expression of embryonic chicken pepsinogen gene, a marker gene of stomach gland epithelial cells.

A gene encoding embryonic chicken pepsinogen (ECPg), a zymogen of the digestive enzyme pepsin, is expressed specifically in epithelial cells of glands of embryonic stage proventriculus (glandular stomach) under the influence of mesenchyme. We found four GATA and one Sox binding motifs in 1.1 kb of the 5' flanking region of the ECPg gene which are essential to the organ-specific expression of the gene. The expression of cGATA-5 and cSox2 in the proventriculus from day 6 to day 12 of incubation was therefore analyzed. cGATA-5 was more strongly expressed in glandular epithelial cells than in luminal epithelial cells, while cSox2 gene expression was weaker in glandular epithelial cells. Using heterologous recombination explants we also discovered that the expression of cGATA-5 and cSox2 in epithelial cells was affected by mesenchyme when the latter induced ECPg gene expression in epithelial cells. Introduction of expression constructs into epithelial cells by electroporation demonstrated that cGATA-5 upregulated transcription of a reporter luciferase gene via a cis element in the 5' flanking region of the ECPg gene. The gel mobility shift assay revealed that the cGATA-5 protein specifically binds to the GATA binding sites. cSox2 downregulated the activity of luciferase but it was not through the Sox binding motif. These results suggest that cGATA-5 positively regulates transcription of the ECPg gene and is involved in spatial regulation of the pepsinogen gene during development., (Copyright 2000 Academic Press.)