Abstract
BackgroundAn increase in cancer cell invasion and microvascular density is associated with a poorer prognosis for patients with endometrial cancer. In endometrial adenocarcinoma F-prostanoid (FP) receptor expression is elevated, along with its ligand prostaglandin (PG)F2α, where it regulates expression and secretion of a host of growth factors and chemokines involved in tumorigenesis. This study investigates the expression, regulation and role of a disintegrin and metalloproteinase with thrombospondin repeat 1 (ADAMTS1) in endometrial adenocarcinoma cells by PGF2α via the FP receptor.MethodsHuman endometrium and adenocarcinoma tissues were obtained in accordance with Lothian Research Ethics Committee guidance with informed patient consent. Expression of ADAMTS1 mRNA and protein in tissues was determined by quantitative RT-PCR analysis and immunohistochemistry. Signal transduction pathways regulating ADAMTS1 expression in Ishikawa cells stably expressing the FP receptor to levels seen in endometrial cancer (FPS cells) were determined by quantitative RT-PCR analysis. In vitro invasion and proliferation assays were performed with FPS cells and human umbilical vein endothelial cells (HUVECs) using conditioned medium (CM) from PGF2α-treated FPS cells from which ADAMTS1 was immunoneutralised and/or recombinant ADAMTS1. The role of endothelial ADAMTS1 in endothelial cell proliferation was confirmed with RNA interference. The data in this study were analysed by T-test or ANOVA.ResultsADAMTS1 mRNA and protein expression is elevated in endometrial adenocarcinoma tissues compared with normal proliferative phase endometrium and is localised to the glandular and vascular cells. Using FPS cells, we show that PGF2α-FP signalling upregulates ADAMTS1 expression via a calmodulin-NFAT-dependent pathway and this promotes epithelial cell invasion through ECM and inhibits endothelial cell proliferation. Furthermore, we show that CM from FPS cells regulates endothelial cell ADAMTS1 expression in a rapid biphasic manner. Using RNA interference we show that endothelial cell ADAMTS1 also negatively regulates cellular proliferation.ConclusionsThese data demonstrate elevated ADAMTS1 expression in endometrial adenocarcinoma. Furthermore we have highlighted a mechanism whereby FP receptor signalling regulates epithelial cell invasion and endothelial cell function via the PGF2α-FP receptor mediated induction of ADAMTS1.
Highlights
An increase in cancer cell invasion and microvascular density is associated with a poorer prognosis for patients with endometrial cancer
Using in vitro model systems of Ishikawa endometrial epithelial cells stably expressing the FP receptor to levels seen in endometrial cancer (FPS cells) and human umbilical vein endothelial cells (HUVECs), we found that ADAMTS1 was regulated in epithelial cells via the PGF2a-FP receptor mediated activation of the calmodulin-NFAT pathway increasing epithelial cell invasion and negatively controlling endothelial cell proliferation
ADAMTS1 expression is elevated in endometrial adenocarcinoma We investigated the mRNA expression of ADAMTS1 in human endometrial adenocarcinoma and normal endometrium from the proliferative phase of the menstrual cycle by Taqman Quantitative RT-PCR analysis
Summary
An increase in cancer cell invasion and microvascular density is associated with a poorer prognosis for patients with endometrial cancer. This study investigates the expression, regulation and role of a disintegrin and metalloproteinase with thrombospondin repeat 1 (ADAMTS1) in endometrial adenocarcinoma cells by PGF2a via the FP receptor. FP receptor can regulate the adhesiveness of endometrial adenocarcinoma cells to the extracellular matrix (ECM) via reorganisation of the actin cytoskeleton and activation of focal adhesion kinase [7,12]. In breast and pancreatic cancer, the matrix metalloproteinase properties of a disintegrin and metalloprotease with a thrombospondin repeat (ADAMTS1), along with its anti-angiogenic role, have been shown to influence metastasis through the promotion of cellular migration and invasion [16,17]. The expression and role of ADAMTS1 in endometrial adenocarcinoma has not been studied
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