期刊
CANCER RESEARCH
卷 69, 期 15, 页码 6339-6346出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-0398
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资金
- NIH [CA106348, CA121105, CA129829, GM065188]
- American Lung Association
- American Cancer Society [RSG-07-156-01-CNE]
- Developmental Research Program
- Career Development Award
- Lung Cancer Specialized Program of Research Excellence at the University of Pittsburgh Cancer Institute [CA090440]
- Flight Attendant Medical Research Institute
- Alliance for Cancer Gene Therapy
- National Basic Research Program of China [2009CB521702]
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]
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