Fibulin-5 suppresses lung cancer invasion by inhibiting matrix metalloproteinase-7 expression.
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.
Yue
Wen
W
Department of Pharmacology and Chemical Biolog, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Sun
Quanhong
Q
Landreneau
Rodney
R
Wu
Chuanyue
C
Siegfried
Jill M
JM
Yu
Jian
J
Zhang
Lin
L
D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D048049:Extracellular Signal-Regulated MAP Kinases; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7