Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer
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Dustin B. Manders2, Hari Annavarapu Kishore1, Adi F. Gazdar3, Patrick W. Keller1, Jun Tsunezumi4, Hiromi Yanagisawa4,5, Jayanthi Lea1,2,* and Ruth Ann Word1,*
1Department of Obstetrics and Gynecology, Green Center for Reproductive Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
3Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
4Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
5Current address: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
Jayanthi Lea, email: [email protected]
Ruth Ann Word, email: [email protected]
Keywords: extracellular matrix; tumor macrophages; MMP-7; cell adhesion
Received: July 20, 2017 Accepted: February 01, 2018 Epub: February 14, 2018 Published: March 06, 2018
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.
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