β-榄香烯调控VEGF-C/VEGFR-3信号通路抑制胃癌裸鼠移植瘤淋巴管生成

β-Elemene inhibits lymphangiogenesis by regulating the VEGF-C/VEGFR-3 signaling in gastric cancer cells xenografted nude mice

目的:探讨β-榄香烯防止胃癌淋巴转移的潜在机制。方法:人胃癌细胞株MKN-45体外培养,不同时间点检测其血管内皮生长因子-C(VEGF-C)表达。建立人胃癌原位移植模型,将裸鼠随机分为模型组,β-榄香烯低、中、高剂量组(25、50、100mg/kg),按设计给药8周后处死动物,称取瘤重,检测微淋巴管密度(LMVD)、VEGF-C及血管内皮生长因子受体-3(VEGFR-3)的表达。结果:VEGF-C在MKN-45细胞株中表达具有随培养时间延长而增高的趋势。与模型组比较,β-榄香烯中、高剂量可以降低裸鼠移植瘤组织中LMVD(P<0.05),下调肿瘤组织中VEGF-C(P<0.05,P<0.01),高剂量可下调VEGFR-3(P<0.05),VEGF-C及VEGFR-3 mRNA和蛋白表达一致。结论:VEGF-C及VEGFR-3是胃癌淋巴管生成的重要调控因子,β-榄香烯通过抑制VEGF-C及VEGFR-3的表达降低淋巴管密度(剂量依赖型)可能是其防止胃癌淋巴转移的机制之一。

Objective： To investigate the underlying mechanisms of β-Elemene in inhibiting lymphatic metastasis. Methods： Human gastric cancer cells MKN-45 were cultured in vitro, VEGF-C expression was detected at different time endpoints. Nude mice were randomly divided into 4 groups： model group, low, medium and high dose of β-Elemene-treated groups which were corresponding to 25, 50, 100mg/kg respectively. Treatment was as scheduled and nude mice were sacrificed after 8 weeks, the tumors were carefully removed and the lymphatic microvessel density （LMVD）, VEGF-C/VEGFR-3 were measured. Results： VEGF-C displayed an increasing tendency with the extending of culture time. Compared with model group, a lower LMVD was detected in [3-Elemene-treated groups （Medium and High dose group; P〈0.05）, the expression of VEGF-C was also down-regulated （Medium and High dose group; P〈0.05, P〈0.01）, however, VEGFR-3 was statistical different only in High dose group （P〈0.05）, the expression of the mRNA was according with the protein of VEGF-C/VEGFR-3. Conclusion： VEGF-C/ VEGFR-3 could paly an important role in lymphangiogenesis in gastric cancer. β-Elemene could restrain lymphangiogenesis in a dose-dependent pattern by manipulating the VEGF-C and VEGFR-3, which could be regarded as a potential mechanisms for its role in the prevention of lymphatic metastasis.