Fibulin-5 suppresses lung cancer invasion by inhibiting matrix metalloproteinase-7 expression

Wen Yue, Quanhong Sun, Rodney Landreneau, Chuanyue Wu, Jill M. Siegfried, Jian Yu, Lin Zhang

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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 downregulated 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.

Original languageEnglish (US)
Pages (from-to)6339-6346
Number of pages8
JournalCancer Research
Volume69
Issue number15
DOIs
StatePublished - Aug 1 2009

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