Carcinogenesis Advance Access originally published online on June 29, 2007
Carcinogenesis 2007 28(11):2274-2281; doi:10.1093/carcin/bgm140
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ECRG2 inhibits cancer cell migration, invasion and metastasis through the down-regulation of uPA/plasmin activity
1 Department of Etiology and Carcinogenesis, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China
2 The Burnham Institute, La Jolla, CA 92037, USA
3 Present address: Department of Laboratory Medicine and Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA
* To whom correspondence should be addressed. Tel: +86 10 87788408; Fax: +86 10 67712368; Email: shlu{at}public.bta.net.cn
Correspondence may also be addressed to Wei Jiang Email: wjiang{at}burnham.org
The esophageal cancer-related gene 2 (ECRG2) is a novel gene that shows sequence similarity to KAZAL-type serine protease inhibitor. In this study, the migration and invasion of PG cancer cells were inhibited by ectopic expression of ECRG2 in vitro, and metastases decreased after injecting PG/pcDNA3.1-ECRG2 cells into the tail veins of nude mice. Control mice were injected with PG/pcDNA3.1 cells. To test the hypothesis that ECRG2 interacts with proteases and inactivates extracellular matrix degradation, binding affinity and co-immunoprecipitation experiments were performed using serum-free conditioned medium. The results showed that ECRG2 bound to two species of urokinase-type plasminogen activator (uPA) with molecular weights of 55 and 33 kDa. Furthermore, analysis of the uPA/plasmin activity showed that expression of ECRG2 reduced proteolysis of the plasmin substrate D-Val-Phe-Lys-p-nitroanilide, which was seen by a decrease of absorbance at 405 nm. Taken together, these results suggested that ECRG2 inhibits aggressiveness of cancer cell, possibly through the down-regulation of uPA/plasmin activity.
Abbreviations: ECM, extracellular matrix; ECRG2, esophageal cancer-related gene 2; MMP, matrix metalloprotease; PAI, plasminogen activator inhibitor; RECK, reversion-inducing cysteine-rich protein with kazal motif; SDS, sodium dodecyl sulfate; uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor
Received January 29, 2007; revised May 17, 2007; accepted June 16, 2007.
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