Edinburgh Research Explorer Interleukin-11 in Endometrial Adenocarcinoma Is Regulated by Prostaglandin F-2 alpha-F-Prostanoid Receptor Interaction via the Calcium-Calcineurin-Nuclear Factor of Activated T Cells Pathway and Negatively Regulated by the Regulator of Calcineurin-1

Is Regulated by F-2 alpha-F-Prostanoid Receptor Interaction via the Calcium-Calcineurin-Nuclear Factor Activated T Pathway Interleukin-11 (IL-11) up-regulates the proliferative and invasive capacity of many cancers. Coexpression of glycoprotein 130 (GP130) and IL-11 receptor (cid:2) (IL-11R (cid:2) ) is necessary for high-affinity binding of IL-11 to IL-11R (cid:2) . This study investigated the expression of IL-11 and role of prostaglandin F 2 (cid:2) -F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11R (cid:2) , and GP130 expression was performed by immunohistochemistry. IL-11 and regulator of calcineurin 1 isoform 4 (RCAN1-4) mRNA and protein expression were determined by real-time RT-PCR and/or enzyme-linked immunosorbent assay/Western blot analysis using Ishikawa endometrial adenocarcinoma cells stably expressing the FP receptor (FPS cells) and endometrial adenocarcinoma explants. IL-11 mRNA expression was significantly elevated in endometrial adenocarcinoma samples compared with normal endometrium the expression of RCAN1-4 lower RCAN1-4 expression grade, levels of RCAN1-4 were lowest in high-grade (poorly differentiated) adenocarcinomas, opposite pattern for IL-11 expression. RCAN1-4 overexpression regulate IL-11 expression in explants vivo our observations using the Ishikawa FPS cell line we found no difference within each grade with to FIGO stage, our data show that RCAN1-4 expression reduces coincident with advancing grade of endometrial adenocarcinoma (ie, from well-differentiated or low-grade to poorly differentiated or high-grade can-cer). These findings suggest that the natural brake created by RCAN1-4 to control calcineurin signaling and cytokine production is defective in high-grade (poorly differentiated) compared with low-grade (well-differentiated) adenocarcinomas. This results in unop-posed PGF 2 (cid:2) -FP receptor signaling via the calcium-calcineurin-NFAT pathway to elevate cytokine production

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