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We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE2 and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE2 is the central factor downstream of TLR4 signaling that promote intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE2 in TLR4-/- mice to see if PGE2 bypasses the protection from colitis-associated tumorigenesis.
Mouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE2 (high dose group, 200 ug, n=8; and low dose group, 100 ug, n=6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE2 during DSS treatment (200 ug, n=5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.
In control mice treated with PBS, the average number of tumors was greater in WT mice (n=13) than in TLR4-/- mice (n=7). High dose but not low dose PGE2 treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 +/- 0.2). By contrast, 75.0% (tumors/animal: 1.5 +/- 1.2, P<0.05) of the high dose group and 33.3% (tumors/animal: 0.3 +/- 0.5) of the low dose group developed dysplasia in TLR4-/- mice. Tumor size was also increased by high dose PGE2 treatment. Endogenous prostanoid synthesis was differentially affected by PGE2 treatment during acute and recovery phases of colitis. Exogenous administration of PGE2 increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE2 treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.
These results highlight the importance of PGE2 as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.
This article was published in the following journal.
Name: BMC gastroenterology
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