(-)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor-vascular endothelial growth factor receptor axis
(-)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor-vascular endothelial growth factor receptor axis
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DOI：
10.1111/j.1349-7006.2009.01241.x
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发表时间：
2009-10-01
期刊：
影响因子：
5.7
通讯作者：
Moriwaki, Hisataka
中科院分区：
文献类型：
--
作者：
Shirakami, Yohei;Shimizu, Masahito;Moriwaki, Hisataka
受体酪氨酸激酶血管内皮生长因子受体(VEGFR)在肝细胞癌的肿瘤血管生成中起重要作用。表没食子儿茶素没食子酸酯(EGCG)是绿茶的主要生物活性成分，通过抑制几种类型的受体酪氨酸激酶的激活来抑制多种人类癌细胞的生长。在这项研究中，我们研究了EGCG对人肝癌细胞中VEGF-VEGFR轴活性的影响。与正常肝细胞相比，一系列人肝癌细胞系中VEGFR-2蛋白的总水平和磷酸化(即活化)形式(p-VEGFR-2)水平升高。与HC细胞相比，EGCG优先抑制表达VEGF-VEGFR轴结构性激活的Huh7肝癌细胞的生长。用EGCG处理Huh7细胞后，VEGFR-2和p-VEGFR-2蛋白的表达呈时间和剂量依赖性下降。经EGCG处理后，HuH7细胞产生的血管内皮细胞生长因子减少。饮用EGCG可显著抑制Huh7裸鼠移植瘤的生长，这与抑制VEGFR-2及其下游信号分子ERK和Akt的激活有关。饮用EGCG还可降低移植瘤中Bclx(L)蛋白和VEGFmRNA的表达。这些发现表明，EGCG至少在一定程度上可以通过抑制VEGF-VEGFR轴发挥其对肝癌细胞的生长抑制作用。因此，EGCG在肝癌的治疗中可能是有用的。(《癌症科学》2009；100：1957-1962)。
The receptor tyrosine kinase vascular endothelial growth factor (VEGF) receptor (VEGFR) plays an important role in tumor angiogenesis of hepatocellular carcinoma (HCC). (-)-Epigallocatechin gallate (EGCG), the major biologically active component of green tea, inhibits growth in a variety of human cancer cells by inhibiting the activation of several types of receptor tyrosine kinases. In this study, we examined the effects of EGCG on the activity of the VEGF-VEGFR axis in human HCC cells. The levels of total and phosphorylated (i.e. activated) form of VEGFR-2 protein (p-VEGFR-2) were observed to increase in a series of human HCC cell lines in comparison to the Hc normal human hepatocytes. EGCG preferentially inhibited the growth of HuH7 HCC cells, which express constitutive activation of the VEGF-VEGFR axis, in comparison to Hc cells. Treatment of HuH7 cells with EGCG caused a time- and dose-dependent decrease in the expression of VEGFR-2 and p-VEGFR-2 proteins. The production of VEGF from HuH7 cells was reduced by treatment with EGCG. Drinking of EGCG significantly inhibited the growth of HuH7 xenografts in nude mice and this was associated with inhibition of the activation of VEGFR-2 and its related downstream signaling molecules, including ERK and Akt. EGCG drinking also decreased the expression of Bcl-x(L) protein and VEGF mRNA in the xenografts. These findings suggest that EGCG can exert, at least in part, its growth-inhibitive effect on HCC cells by inhibiting the VEGF-VEGFR axis. EGCG might therefore be useful in the treatment of HCC. (Cancer Sci 2009; 100: 1957-1962).