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, Ruth Ann Word

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14251-14267
Number of pages17
JournalOncotarget
Volume9
Issue number18
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Cell adhesion
  • Extracellular matrix
  • MMP-7
  • Tumor macrophages

ASJC Scopus subject areas

  • Oncology

Cite this

Manders, D. B., Kishore, H. A., Gazdar, A. F., Keller, P. W., Tsunezumi, J., Yanagisawa, H., Lea, J., & Word, R. A. (2018). Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer. Oncotarget, 9(18), 14251-14267. https://doi.org/10.18632/oncotarget.24484