Significance of prostaglandin E₂ signaling in the carcinogenesis of ulcerative colitis

Background The incidence of colorectal cancer arising in the setting of long-standing inflammatory bowel disease (IBD) has been increasing with the rising prevalence of ulcerative colitis (UC). Patients with long-standing UC have an approximately five-fold higher risk of colorectal cancer (CRC) compared with the general population. However, the molecular mechanisms underlying UC-associated carcinogenesis remain poorly defined. Prostaglandin E₂ (PGE₂) signaling is one of a key mediators of inflammation, and elevated PGE₂ levels have been observed in inflamed colonic tissue of UC patients. PGE₂ signaling also promotes tumor proliferation and metastasis in several cancer types. Objective To clarify the involvement of PGE₂ signaling in UC-associated carcinogenesis by examining the expression of PGE₂ receptors EP2 and EP4 in UC-related neoplastic lesions. Methods Forty-one patients who underwent the surgical operation for UC-associated neoplasia (16 dysplasia, 25 carcinoma) at our institution were included. Paraffin-embedded sections of dysplastic and cancerous lesions were subjected to immunohistochemical staining for EP2 and EP4. Expression intensity and proportion of EP2/EP4 were scored, and correlations between EP2/EP4receptor expression and clinicopathological parameters were analyzed. Results Cancer tissues showed higher expression of EP2 and EP4 than dysplastic tissues in UC-associated neoplasia. Expression of either receptor (EP2 or EP4) was more frequent (p = 0.0678) in cancer lesions (81.5%, 22/27) compared with dysplastic lesions (50.0%, 7/14). EP2 positivity was observed in 66.7% of cancer lesions (18/27) and 42.9% of dysplastic lesions (6/14) (p = 0.189). EP4 expression tended to be higher (p = 0.0516) in cancer lesions (63.0%, 17/27) than in dysplastic lesions (28.6%, 4/14) (p = 0.0516) while EP2 positivity was not (p = 0.189;observed in 66.7% of cancer lesions (18/27) and 42.9% of dysplastic lesions) (6/14) (p = 0.189). Expression of either receptor (EP2 or EP4) was more frequent in cancer lesions (81.5%, 22/27) compared with dysplastic lesions (50.0%, 7/14) (p = 0.0678). In contrast, EP2 or EP4 Receptor expression was not significantly associated with cancer tumor stage, depth of invasion, or prognosis. Conclusion These findings suggest that PGE₂ signaling, particularly through the EP4 receptor, may might contribute to the carcinogenesis in UC ulcerative colitis. EP4-mediated pathways may represent potential therapeutic or preventive targets in UC-associated CRC colorectal cancer.