Abstract
Fibulin 5 (FBLN5) is an extracellular matrix glycoprotein that suppresses matrix metalloprotease 9 (MMP-9), angiogenesis and epithelial cell motility. Here, we investigated the regulation and function of FBLN5 in epithelial ovarian cancer (EOC). FBLN5 mRNA was down-regulated 5-fold in EOC relative to benign ovary. Not surprisingly, MMP9 mRNA and enzyme activity were increased significantly, and inversely correlated with FBLN5 gene expression. FBLN5 degradation products of 52.8 and 41.3 kDa were increased substantially in EOC. We identified two candidate proteases (serine elastase and MMP-7, but not MMP-9) that cleave FBLN5. MMP-7, but not neutrophil elastase, gene expression was increased dramatically in EOC. Recombinant FBLN5 significantly inhibited adhesion of EOC cells to both laminin and collagen I. Finally, using immunohistochemistry, we found immunoreactive FBLN5 within tumor macrophages throughout human EOC tumors. This work indicates that FBLN5 is degraded in EOC most likely by proteases enriched in macrophages of the tumor microenvironment. Proteolysis of FBLN5 serves as a mechanism to promote cell adhesion and local metastasis of ovarian cancer cells. Promotion of a stable ECM with intact FBLN5 in the tumor matrix may serve as a novel therapeutic adjunct to prevent spread of ovarian cancer.
Highlights
Ovarian cancer is the second most common gynecologic malignancy in the US, accounting for approximately 22,000 new cases per year [1]
To determine if fibulin genes are differentially regulated in ovarian cancer tissue relative to benign ovarian tissue, RNA was extracted from tissue samples and relative mRNA levels of FBLN1, FBLN2, FBLN3, FBLN4, Fibulin 5 (FBLN5) and FBLN7 were quantified using qPCR
We considered the possibility that matrix proteins may be globally downregulated in epithelial ovarian cancer (EOC) due to a disproportionate number of ovarian epithelial cells relative to matrix-secreting stromal fibroblasts
Summary
Ovarian cancer is the second most common gynecologic malignancy in the US, accounting for approximately 22,000 new cases per year [1]. It has been shown to be prominent in blood vessel walls and in the basement membrane underlying epithelial cells [10] It is a crucial protein in the formation of elastic fibers as it tethers tropoelastin to microfibrils where tropoelastin is cross-linked by lysyl oxidases to form mature elastic fibers [11]. It mediates endothelial cell adhesion through its integrin binding domain, and has been shown to be dramatically induced in vascular endothelial and smooth muscle cells in response to injury [12]. FBLN5 antagonizes VEGF signaling resulting in diminution of VEGF-induced proliferation and migration of endothelial cells [13]
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