Oncotarget

Research Papers:

Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer

Dustin B. Manders, Hari Annavarapu Kishore, Adi F. Gazdar, Patrick W. Keller, Jun Tsunezumi, Hiromi Yanagisawa, Jayanthi Lea _ and Ruth Ann Word

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Oncotarget. 2018; 9:14251-14267. https://doi.org/10.18632/oncotarget.24484

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Abstract

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

*Co-senior authors

Correspondence to:

Jayanthi Lea, email: jayanthi.lea@UTSouthwestern.edu

Ruth Ann Word, email: ruth.word@utsouthwestern.edu

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

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.


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