Microsomal
PGE2 synthase-1 (mPGES-1), the terminal
enzyme in the formation of inducible
PGE2, represents a potential target for
cancer chemoprevention. We have previously shown that genetic abrogation of mPGES-1 significantly suppresses
tumorigenesis in two preclinical models of
intestinal cancer. In this study, we examined the role of mPGES-1 during colon
tumorigenesis in the presence of
dextran sulfate sodium (DSS)-induced inflammatory microenvironment. Using Apc (Δ14/+) in which the mPGES-1 gene is either wild-type (D14:WT) or deleted (D14:KO), we report that mPGES-1 deficiency enhances sensitivity to acute mucosal injury. As a result of the increased epithelial damage, protection against
adenoma formation is unexpectedly compromised in the D14:KO mice. Examining the DSS-induced acute injury, cryptal structures are formed within inflamed areas of colonic mucosa of both genotypes that display the hallmarks of early
neoplasia. When acute epithelial injury is balanced by titration of DSS exposures, however, these small cryptal lesions progress rapidly to
adenomas in the D14:WT mice. Given that mPGES-1 is highly expressed within the intestinal stroma under the inflammatory conditions of DSS-induced ulceration, we propose a complex and dual role for inducible
PGE2 synthesis within the colonic mucosa. Our data suggest that inducible
PGE2 is critical for the maintenance of an intact colonic epithelial barrier, while promoting epithelial regeneration. This function is exploited during neoplastic transformation in Apc (Δ14/+) mice as
PGE2 contributes to the growth and expansion of the early initiated cryptal structures. Taken together, inducible
PGE2 plays a complex role in
inflammation-associated
cancers that requires further analysis. Inducible
PGE2 production by mPGES-1 is critical for the colonic mucosal homeostasis. This function is exploited in the presence of the neoplastic transformation in Apc (Δ14/+) mice as
PGE2 contributes to the growth and expansion of the early cryptal structures.