Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
Am J Pathol. 2010 Jan;176(1):435-45. doi: 10.2353/ajpath.2010.090403. Epub 2009 Dec 11.
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-11Ralpha) is necessary for high-affinity binding of IL-11 to IL-11Ralpha. This study investigated the expression of IL-11 and role of prostaglandin F(2alpha)-F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11Ralpha, 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-11Ralpha, and GP130 in the neoplastic glandular epithelium of endometrial adenocarcinomas. Prostaglandin F(2alpha)-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.
白细胞介素-11（IL-11）上调许多癌症的增殖和侵袭能力。糖蛋白 130（GP130）和白细胞介素-11 受体 alpha（IL-11Ralpha）的共表达对于 IL-11 与 IL-11Ralpha 的高亲和力结合是必要的。本研究调查了白细胞介素-11 的表达及其在调节子宫内膜腺癌细胞中白细胞介素-11 表达中的作用，以及前列腺素 F(2alpha)-F-前列腺素受体（FP 受体）信号。通过免疫组织化学检测白细胞介素-11、白细胞介素-11 受体 alpha 和 GP130 的表达。使用稳定表达 FP 受体（FPS 细胞）和子宫内膜腺癌外植体的 Ishikawa 子宫内膜腺癌细胞，通过实时 RT-PCR 和/或酶联免疫吸附试验/Western blot 分析确定白细胞介素-11 和钙调神经磷酸酶 1 同工型 4（RCAN1-4）mRNA 和蛋白表达。与正常子宫内膜相比，子宫内膜腺癌样本中白细胞介素-11 mRNA 的表达显著升高，并随着肿瘤分级的增加而增加。白细胞介素-11 蛋白表达与 FP 受体、白细胞介素-11Ralpha 和 GP130 一起定位于子宫内膜腺癌的肿瘤腺上皮中。前列腺素 F(2alpha)-FP 受体信号通过 Gq-蛋白激酶 C-钙-钙调神经磷酸酶-活化 T 细胞核因子依赖的方式显著增加 FPS 细胞中白细胞介素-11 mRNA 和蛋白的表达。已知钙调神经磷酸酶信号通路受 RCAN（RCAN1-4）调控。事实上，与正常子宫内膜相比，高分化子宫内膜腺癌中 RCAN1-4 的表达显著升高，并发现其随着肿瘤分级的降低而降低，并在体外负调控白细胞介素-11 的表达。本研究强调了通过 FP 受体通过钙调神经磷酸酶-活化 T 细胞核因子途径调节子宫内膜腺癌细胞中白细胞介素-11 表达的新机制。
