Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis
Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis
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DOI：
10.1158/1535-7163.mct-06-0798
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发表时间：
2007-12
影响因子：
5.7
通讯作者：
B. Zhu;Lei Lu;Weibin Cai;Xia Yang;Chaoyang Li;Zhonghan Yang;Wenhua Zhan;Jian-xing Ma;G. Gao
中科院分区：
文献类型：
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作者：
B. Zhu;Lei Lu;Weibin Cai;Xia Yang;Chaoyang Li;Zhonghan Yang;Wenhua Zhan;Jian-xing Ma;G. Gao
激肽释放酶结合蛋白（KBP）已被确定为内源性血管生成抑制剂。我们先前的研究表明，KBP通过下调内皮细胞中的血管内皮生长因子（VEGF）来抑制大鼠视网膜新生血管形成。然而，其抑制胃癌的抗血管生成潜力和对肿瘤细胞中VEGF的影响尚未阐明。本研究旨在探讨KBP对胃癌生长的影响及其可能的分子机制。重组KBP呈剂量依赖性地抑制内皮细胞的增殖和诱导凋亡，但对胃癌细胞SGC-7901的增殖和凋亡无影响。腹腔注射KBP导致异位和原位胃癌异种移植物的生长抑制分别为61.4%和52.3%。KBP处理的肿瘤组织中的微血管密度显著降低，表明KBP通过抗血管生成抑制肿瘤生长。KBP可下调胃癌细胞和胃癌移植瘤中血管生成因子VEGF的表达和释放。KBP还降低了SGC-7901细胞中VEGF的RNA水平，从而表明在转录水平上进行了调节。因此，低氧诱导因子1α（HIF-1α），VEGF表达的关键转录因子，在KBP处理的SGC-7901细胞中进行了检测。KBP降低了HIF-1α蛋白水平和核转位，这可能是KBP下调VEGF转录的机制之一。KBP通过抑制HIF-1α下调肿瘤细胞VEGF的表达和释放，从而减弱VEGF对肿瘤组织内皮细胞增殖和血管通透性的旁分泌作用，可能是其抗血管生成和抗肿瘤作用的新机制。[Mol Cancer Ther 2007;6（12）：3297-306]
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 1α (HIF-1α), a crucial transcriptional factor for VEGF expression, was examined in SGC-7901 cells treated by KBP. KBP reduced HIF-1α 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-1α, 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]