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Research Articles: Therapeutics, Targets, and Development

Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis

¹ Department of Biochemistry, Zhongshan Medical School; ² Department of Gastrointestinopancreatic Surgery, First Affiliated Hospital; and ³ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; and ⁴ Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Requests for reprints: Guoquan Gao, Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, No. 74 Zhongshan Road II, Guangzhou 510089, China. Phone: 86-20-87331575; Fax: 86-20-87331575. E-mail: gaogq{at}mail.sysu.edu.cn

Abstract

Kallikrein-binding protein (KBP) has been identified as an endogenous angiogenic inhibitor. We previously showed that KBP inhibited rat retinal neovascularization by down-regulation of vascular endothelial growth factor (VEGF) in endothelial cells. However, its antiangiogenic potential for inhibition of gastric carcinoma and the effect on VEGF in tumor cells have not been elucidated. The present study was designed to investigate the effect of KBP on growth of gastric carcinoma and the possible molecular mechanism. Recombinant KBP dose dependently inhibited proliferation and induced apoptosis of endothelial cells, but no effect on proliferation and apoptosis of SGC-7901 gastric carcinoma cells. I.p. injection of KBP resulted in growth inhibition of both heterotopic and orthotopic gastric carcinoma xenografts at 61.4% and 52.3%, respectively. Microvessel density in tumor tissues treated with KBP was significantly decreased, suggesting that KBP suppressed tumor growth by antiangiogenesis. The expression and release of VEGF, a major angiogenic stimulator, were down-regulated by KBP in SGC-7901 cells and gastric carcinoma xenografts. RNA levels of VEGF in SGC-7901 cells were also decreased by KBP, thus suggesting the regulation at the transcriptional level. Therefore, hypoxia-inducible factor 1 (HIF-1), a crucial transcriptional factor for VEGF expression, was examined in SGC-7901 cells treated by KBP. KBP reduced HIF-1 protein level and nuclear translocation, which may be responsible for the down-regulation of VEGF transcription. Down-regulation of VEGF expression and release in tumor cells through inhibiting HIF-1, thus attenuating the paracrine effect of VEGF on endothelial cell proliferation and vascular permeability in tumor tissues, may represent a novel mechanism for the antiangiogenic and antitumor activity of KBP. [Mol Cancer Ther 2007;6(12):3297–306]

Grant support: National Nature Science Foundation of China grants 30370313, 30570372, 30600724, and 30700120; China Medical Board of New York, Inc./Sun Yat-sen University of Medical Sciences Scholar Project, grant 98-677; Program for New Century Excellent Talents in University, grant NCET-040792; Team Project of Nature Science Foundation of Guangdong Province, China, grant 06201946; Key Sci-tech Research Project of Guangdong Province, China, grants 2005A10902003 and 2006B35502001; Nature Science Foundation of Guangdong Province, China, grant 06021260; Key Sci-tech Research Project of Guangzhou Municipality, Guangdong Province, China, grants 2005Z3-E4031, 2006Z3-E4111, and 2007Z3-E5041; and NIH grants EY015650 and EY12231.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: B. Zhu and L. Lu contributed equally to this work.

⁵ Supplementary material for this article is available at Molecular Csncer Therapeutics Online (http://mct.aacrjournals.org/).

Received 12/27/06; revised 10/ 7/07; accepted 11/ 1/07.