Abstract 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. Citation Format: Tatsunari Fukuoka, Masakazu Yashiro, Hiroaki Kasashima, Nobuhiro Naito, Iguru Omori, Yasuhiro Fukui, Yuki Seki, Kenji Kuroda, Yuichiro Miki, Mami Yoshii, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Kiyoshi Maeda. Significance of prostaglandin E2 signaling in the carcinogenesis of ulcerative colitis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 689.
Fukuoka et al. (Fri,) studied this question.