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Originally published online as doi:10.2353/ajpath.2010.090403 on December 11, 2009

Published online before print December 11, 2009
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(American Journal of Pathology. 2010;176:435-445.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.090403

Interleukin-11 in Endometrial Adenocarcinoma Is Regulated by Prostaglandin F2{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

Kurt J. Sales*, Vivien Grant*, Ian H. Cook*, David Maldonado-Pérez*{dagger}, Richard A. Anderson{dagger}, Alistair R.W. Williams{ddagger} and Henry N. Jabbour*

From the Medical Research Council Human Reproductive Sciences Unit,* and the Departments of Reproductive and Developmental Sciences,{dagger} and Pathology,{ddagger} The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

Interleukin-11 (IL-11) up-regulates the proliferative and invasive capacity of many cancers. Coexpression of glycoprotein 130 (GP130) and IL-11 receptor {alpha} (IL-11R{alpha}) is necessary for high-affinity binding of IL-11 to IL-11R{alpha}. This study investigated the expression of IL-11 and role of prostaglandin F2{alpha}-F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11R{alpha}, 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 and increased with tumor grade. IL-11 protein expression localized with FP receptor, IL-11R{alpha}, and GP130 in the neoplastic glandular epithelium of endometrial adenocarcinomas. Prostaglandin F2{alpha}-FP receptor signaling significantly elevated the expression of IL-11 mRNA and protein in a Gq-protein kinase C-calcium-calcineurin-nuclear factor of activated T cells-dependent manner in FPS cells. The calcineurin signaling pathway is known to be controlled by the RCAN (RCAN1-4). Indeed, RCAN1-4 expression was significantly elevated in well-differentiated endometrial adenocarcinoma compared with normal endometrium and was found to decrease with tumor grade and negatively regulate IL-11 expression in vitro. This study has highlighted a new mechanism regulating IL-11 expression in endometrial adenocarcinoma cells by the FP receptor via the calcium-calcineurin-nuclear factor of activated T cells pathway.






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