Inhibition of tumor growth and vasculogenic mimicry by cucumin through downregulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model
Inhibition of tumor growth and vasculogenic mimicry by cucumin through downregulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model
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DOI：
10.4161/cbt.11.2.13842
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发表时间：
2011-01-15
影响因子：
3.6
通讯作者：
Li, Xiao-Rong
中科院分区：
文献类型：
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作者：
Chen, Lu-Xia;He, Yan-Jin;Li, Xiao-Rong
本研究旨在探讨姜黄素在小鼠脉络膜黑色素瘤模型中抑制肿瘤生长和减少血管生成拟态(VM)的潜在机制。60只小鼠视网膜下注射B16F10细胞，随机分为治疗组和对照组。治疗组给予姜黄素100 mg/kg，1次/d，从d3(接种当天定为d0)开始给药18d，对照组给予等量泊洛沙姆-F68。免疫组织化学和组织化学双重染色检测不同的血供模式。免疫组织化学方法检测肿瘤组织中上皮细胞激酶(EphA2)、磷脂酰肌醇-3-激酶(PI3K)、基质金属蛋白酶-2和-9(MMP2、MMP9)的表达，实时定量聚合酶链式反应(Real-time PCR)检测其基因表达水平。结果表明，姜黄素能显著缩小肿瘤体积(p=0.000)，显著减少Vm(p=0.000)、马赛克血管(p=0.031)和内皮依赖性血管(p=0.000)的数量(p=0.001)。治疗组EphA2、PI3K、基质金属蛋白酶-2和-9的表达水平也低于对照组(p=0.001)，治疗组的表达水平也低于对照组(p=0.000)。综上所述，姜黄素通过调节血管生成因子抑制移植黑色素瘤Vm通道的生长，这可能与下调EphA2/PI3K/MMPs信号通路有关。因此，姜黄素有可能成为脉络膜黑色素瘤Vm的临床抑制剂。
This study aims to investigate the underlying mechanism by which curcumin inhibits tumor growth and reduces vasculogenic mimicry (VM) in a murine choroidal melanoma model. Sixty mice were given subretinal injection with B16F10 cells and divided into a treatment and a control group. Curcumin was administered to the treatment group once a day at a dose of 100 mg/kg for 18 days starting at d3 (the day of inoculation is designated as d0); an equivalent volume of poloxamer-F68 was administered to the control group. Immunohistochemical and histochemical double staining were ued to detect the different blood supply patterns. The amounts of epithelial cell kinase (EphA2), phosphatidylinositol-3-kinase (PI3K) and matrixmetalloproteinase-2 and -9 (MMP-2, MMP-9) proteins expressed in the tumor tissue were analyzed using immunohistochemical staining; mRNA levels were measured using real-time PCR analysis. Results indicate that the tumor volume is reduced (p = 0.000) and that the numbers of VM (p = 0.000), mosaic vessels (p = 0.031) and endothelium-dependent vessels (p = 0.000) are significantly decreased by curcumin (p = 0.001). The expression levels of EphA2, PI3K, MMP-2 and -9 are also lower in the treatment group than in the control group (p = 0.001); similarly, mRNA levels in the treatment group are lower than those in the control group (p = 0.000). In conclusion, curcumin has the ability to inhibit the growth of engrafted melanoma VM channels through the regulation of vasculogenic factors that could be related to the downregulation of the EphA2/PI3K/MMPs signaling pathway. Thus, curcumin has the potential of being a clinical inhibitor of VM of choroidal melanoma.