|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1999 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1998 : ¥1,800,000 (Direct Cost : ¥1,800,000)
The investigators explored factors influencing differentiation and morphogenesis of gastric epithelium using gastric cell lines (RGM1, GSM06, GSM10, MKN28, MKN45) and cell lines derived from intestinal tract. The expression or occurrence of the above factors in human gastric mucosa was also investigated.
In the first exploration, influences of retinoic acids and short chain fatty acids on phenotypes of gastric epithelial cells were examined. Butyrate, but not retinoic acids, induces morphologic changes and intracellular granules in untransformed RGM1 rat gastric epithelial cells. Butyrate also induces morphologic changes and apoptosis in mouse-derived GSM cells. Programmed cell death induced by butyrate was abolished by cox-2 overexpression in another intestinal cells. Consequently, in the second investigation, expression of COX-2 in gastric mucosa, gastric premalignant lesions and gastric adenocarcinomas was examined using immunohistochemistry. Gastric epithelia and subepithelial cells
expressed COX-2 in subjects with H. pylori-infection. The epithelia with intestinal metaplasia also expressed COX-2 in humans regardless of the bacterial infection, suggesting a role of this isozyme in disregulated differentiation and gastric carcinogenesis. Further over-expression of COX-2 was demonstrated in gastric cancers. Both in vitro and iv vivo studies clearly showed that COX-2 is an important regulatory factor in production of angiogenic factors, VEGF, bFGF, NOS, and endothelins. Antisense oligonucleotides for cox-2 and COX-2 specific inhibitor suppressed the above angiogenic factors in cell lines expressing this isozyme.
In the final investigation, a role of COX-2 in gastric epithelial morphogenesis was demonstrated in RGM1 cells in 3-dimensional culture. Glandular morphology was developed in these cells after stimulation with TGFα.COX-2 inhibitors and cox-2 anti-sense oligonucleotides suppressed the morphological alteration in RGM1 cells. In conclusion, cox-2 have important roles in differentiation and morphogenesis in gastric epithelium. Less