Studies on expression and regulation of phospholipase A2 and cyclooxygenase 2 in gastrointestinal tissues with special reference to colorectal cancer

Sammanfattning: The phospholipases A2 (PLA2s) are phospholipid hydrolyzing enzymes that in mammalian cells exist in several different isoform including cytosolic PLA2 (cPLA2), group I PLA2 (PLA2-I) and group II PLA2 (PLA2-ll). PLA2 is involved in production of inflammatory mediators, membrane remodelling, digestive functions and stimulation of prolifemtion. In addition. PLA2 supplies cyclooxygenase COX-1 and COX-2 with arachidonic acid for production of eicosanoids.Increased COX-2 expression and high concentrations of prostaglandins have been found in human colorectal adenocarcinomas and in rat colonic twnours. Studies implicate that there is a link between the tumourigenic effect of the tumour suppressor gene adenomatous polyposis coli (APC) and COX-2 up-regulation in mouse intestinal neoplasms. Mutations of the human APC gene are frequent in both sporadic and familial colorectal cancer and result in activation of p-catenin!T cell factor-4 (Tcf-4) mediated transcription of target genes which may contribute to colorectal tumourigenesis.The ontogenic development of rat gastrointestinal PLA2-I and PLA2-II and the influence of the exogenous glucocorticoid cortisone acetate were studied. The ontogeny of rat glandular stomach PLA2-I and PLA2-II gene expression is similar and seems to follow the general postnatal development of the gastrointestinal tract PLA2-II gene expression is different in the glandular stomach compared to ileum and forestomach during the neonatal period. Administration of the cortisone acetate, during the neonatal period, induced PLA2-I and PLA2-II gene expression in glandular stomach and ileum, respectively, au effect that may be related to maturation of the gastrointestinal tract.Gene expression of PLA2-II, cPLA2 and COX-2, protein levels of COX-2 and mutational analysis of APC were investigated in human colorectal tumours. COX-2 was dramatically up-regulated in tumours located in rectum and associated with the presence of APC mutations. Tcf-4 consensus sequences found in the COX-2 promoter were activated but APC/P-catenin/fcf-4 pathway may partly be involved in transcriptional regulation of the COX-2 gene. Neither induction of PLA2-II nor correlation in gene expression between cPLA2 and COX-2 were observed. 'These observations imply that other enzymes than PLA2 contribute to generate arachidonic acid for COX-2 mediated eicosanoid metabolism aud that PLA2-II seems to play a minor or no role in hllltlan colorectal cancer.