Suppression of Intestinal Polyposis inApc Δ716 Knockout Mice by an Additional Mutation in the Cytosolic Phospholipase A2Gene

Abstract

Arachidonic acid is a precursor for biosynthesis of eicosanoids, including prostaglandins, thromboxanes, leukotrienes, and lipoxins. Cytosolic phospholipase A2 (cPLA2) plays a key role in the release of arachidonic acid as the substrate of cyclooxygenase-1 (COX-1) or COX-2. We found that the level of cPLA2 mRNA was markedly elevated in the polyps and correlated with the polyp size in the small intestine of theApc Δ716 knockout mouse, a model for human familial adenomatous polyposis. To determine the role of cPLA2 in intestinal tumorigenesis, we then introduced a cPLA2 gene mutation intoApc Δ716 mice. In the compound mutant mice, the size of the small intestinal polyps was reduced significantly, although the numbers remained unchanged. These results provide direct genetic evidence that cPLA2 plays a key role in the expansion of polyps in the small intestine rather than in the initiation process. In contrast, colonic polyps were not affected in either size or number. Interestingly, group X sPLA2 was constitutively expressed in the colon at much higher levels than in the small intestine. These results suggest that in the colon, group X sPLA2 supplies arachidonic acid in both the normal epithelium and the polyps even in the absence of cPLA2.