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Fibulin-5 Suppresses Lung Cancer Invasion by Inhibiting Matrix Metalloproteinase-7 Expression

Departments of ¹ Pharmacology and Chemical Biology, ² Pathology, and ³ Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: Lin Zhang, the University of Pittsburgh Cancer Institute Research Pavilion, Room 2.42d, Hillman Cancer Center, 5117 Centre Avenue, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213. Phone: 412-623-1009; Fax: 412-623-7778; E-mail: zhanglx{at}upmc.edu.

Key Words: Fibulin-5 • MMP-7 • integrin • invasion • lung cancer

The high mortality rate of lung cancer is largely due to the spread of disease to other organs. However, the molecular changes driving lung cancer invasion and metastasis remain unclear. In this study, we identified fibulin-5, a vascular ligand for integrin receptors, as a suppressor of lung cancer invasion and metastasis. Fibulin-5 was silenced by promoter hypermethylation in a majority of lung cancer cell lines and primary tumors. It inhibited lung cancer cell invasion and down-regulated matrix metalloproteinase-7 (MMP-7), which promoted lung cancer cell invasion. Knockdown of fibulin-5 was sufficient to stimulate cell invasion and MMP-7 expression. The expression levels of fibulin-5 and MMP-7 were inversely correlated in lung tumors. Suppression of MMP-7 expression by fibulin-5 was mediated by an integrin-binding RGD motif via the extracellular signal-regulated kinase (ERK) pathway. Furthermore, overexpression of fibulin-5 in H460 lung cancer cells inhibited metastasis in mice. Collectively, these results suggest that epigenetic silencing of fibulin-5 promotes lung cancer invasion and metastasis by activating MMP-7 expression through the ERK pathway. [Cancer Res 2009;69(15):6339–46]