GdCl3 suppresses the malignant potential of hepatocellular carcinoma by inhibiting the expression of CD206 in tumor-associated macrophages
GdCl3 suppresses the malignant potential of hepatocellular carcinoma by inhibiting the expression of CD206 in tumor-associated macrophages
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GdCl3通过抑制肿瘤相关巨噬细胞中CD206的表达来抑制肝细胞癌的恶性潜能
DOI：
10.3892/or.2015.4268
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发表时间：
2015-11-01
期刊：
影响因子：
4.2
通讯作者：
Luo, Fang
中科院分区：
文献类型：
--
作者：
Zhu, Fangyu;Li, Xiangnan;Luo, Fang
本研究旨在探讨CD206在肿瘤相关巨噬细胞(TAMs)中的表达是否与原发性肝细胞癌(HCC)的预后有关，并探讨GdCl3对肝癌的影响。用肝组织芯片检测CD206在肝细胞癌组织和癌旁组织中的表达。观察GdCl3对RAW264.7细胞CD206表达的影响。用RT-PCR、Western blotting和免疫组织化学方法检测靶基因的表达。用Transwell系统评价肝癌细胞的侵袭力。最后，我们用N-亚硝基二乙胺(DEN)建立了小鼠肝癌模型，以确定GdCl3对肝癌的影响。肝组织芯片分析显示CD206在肝细胞癌组织中高表达，而在PEN癌组织中表达水平较低。我们发现GdCl3对刺激的RAW264.7细胞M2巨噬细胞表型中CD206的表达有抑制作用，IC10值为0.07mUg/mU L。此外，GdCl3还能诱导RAW264.7细胞发生凋亡。RAW264.7细胞培养上清液中加入GdCl3后，与对照组相比，细胞侵袭能力明显降低。相应地，在IL-4刺激的细胞中，GdCl3处理增加了上皮-间充质转化(EMT)相关蛋白E-cadherin的表达，而N-cadherin、twist和Snail的表达降低。此外，GdCl3治疗抑制了DEN诱导的肝癌小鼠的肝癌进展，可能是通过下调CD206的表达。我们的发现表明CD206是一个潜在的预测肝癌预后的生物标志物，GdCl3通过下调CD206在TAM中的表达来抑制肝癌的进展。
In the present study, we aimed to ascertain whether there is a correlation between CD206 expression in tumor associated-macrophages (TAMs) and the prognosis of primary hepatocellular carcinomas (HCC) and we investigated the effect of GdCl3 on HCC. The expression of CD206 in HCC tumor tissues and pen-carcinoma tissues was measured using an array for liver tissues. The effects of GdCl3 on CD206 expression were examined in stimulated RAW264.7 cells. Target gene expression was evaluated by RT-PCR, western blotting and immunohistochemistry. The Transwell system was used to assess the invasiveness of HCC cells. Finally, we established a mouse model for HCC using N-nitrosodiethylamine (DEN) to determine the effect of GdCl3 on HCC. Liver tissue array analysis revealed that CD206 was highly expressed in the HCC tissues compared to the level in pen-carcinoma tissue. We found that GdCl3 suppressed the expression of CD206 in the M2 macrophage phenotype of stimulated RAW264.7 cells with an IC10 value of 0.07 mu g/mu l. In addition, GdCl3 also induced cell apoptosis in the RAW264.7 cells. Addition of GdCl3 into the culture medium of RAW264.7 cells markedly reduced the invasive ability of Hepal-6 cells compared to the control cells. Accordingly, GdCl3 treatment increased the expression of the epithelial-mesenchymal transition (EMT)-related protein E-cadherin while expression of N-cadherin, TWIST and Snail was reduced in IL-4-stimulated cells. Moreover, GdCl3 treatment inhibited HCC progression in DEN-induced HCC mice, possibly by downregulating CD206. Our findings indicate that CD206 is a potential biomarker for predicting HCC prognosis and that GdCl3 suppresses HCC progression by downregulating the expression of CD206 in TAMs.