Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-kappa B/Slug pathway
Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-kappa B/Slug pathway
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活化的巨噬细胞通过 NF-kappa B/Slug 通路下调肝细胞癌细胞中 E-cadherin 的表达
DOI：
10.1007/s13277-014-2159-7
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Shi Yongyu
中科院分区：
文献类型：
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作者：
Wang Xianteng;Wang Hao;Li Guosheng;Song Yonghong;Wang Shurong;Zhu Faliang;Guo Chun;Zhang Lining;Shi Yongyu
肝细胞癌是一种侵袭性的恶性肿瘤，主要是由于转移或术后复发。E-钙粘蛋白在肝细胞癌组织中的表达显著降低，其表达下调与肝细胞癌的侵袭和转移有关。先前的研究表明，活化的巨噬细胞上清液可以下调肝癌细胞中E-钙粘蛋白的表达。已知的部分分子机制是酪氨酸激酶c-Src-和EGFR使β-连环蛋白和E-钙粘蛋白磷酸化，导致E-钙粘蛋白/β-连环蛋白复合体失稳。本研究的目的是阐明激活的巨噬细胞下调E-钙粘蛋白表达的其他机制。采用免疫组织化学双染色方法检测肝细胞癌组织中E-钙粘附素的表达及巨噬细胞的浸润情况，并在体外实验中探讨巨噬细胞与E-钙粘附素表达的关系。我们发现，在肝细胞癌组织中，E-钙粘附素的表达减少与巨噬细胞沿瘤巢和间质之间的边界渗透有关。此外，肝癌细胞与THP-1细胞来源的巨噬细胞共培养时，E-钙粘附素的蛋白表达显著降低。同样，在与THP-1分化的巨噬细胞共培养的癌细胞中，E-钙粘素的mRNA表达也降低。此外，在用THP-1分化的巨噬细胞条件培养液培养的癌细胞中，E-cadherin的表达下调的同时，slug的表达也上调。阻断NF-κB信号通路后，E-钙粘素和slug表达的变化被抑制。提示巨噬细胞通过NF-κB/slug途径降低E-钙粘素在肝细胞癌中的表达。
Hepatocellular carcinomas are an aggressive malignancy mainly due to metastasis or postsurgical recurrence. Expression of E-cadherin is strongly reduced in Hepatocellular carcinoma (HCC) tissues, and its downregulation is connected to invasiveness and metastasis in hepatocellular carcinomas. The previous study showed that the supernatant from activated macrophages can downregulate the expression of E-cadherin in HCC cells. The partial known molecular mechanism is that tyrosine kinases c-Src- and EGFR phosphorylate β-catenin and E-cadherin leading to destabilization of E-cadherin/β-catenin complex. The aim of this study is to clarify other mechanism by which activated macrophages downregulate the expression of E-cadherin. We detect the expression of E-cadherin and macrophage infiltration in hepatocellular carcinoma tissues by double-staining immunohistochemistry and evaluate the relationship between macrophages and E-cadherin expression in hepatocellular carcinoma cells in vitro experiments. We found that reduced expression of E-cadherin was associated with macrophage infiltration along the border between the tumor nest and stroma in hepatocellular carcinoma tissues. Besides, protein expression of E-cadherin was significantly decreased in hepatocellular carcinoma cells co-cultured with macrophages derived from THP-1 cells. Consistently, mRNA expression of E-cadherin was also decreased in cancer cells co-cultured with THP-1-differentiated macrophages. Moreover, the downregulation of E-cadherin expression was companied by upregulation of Slug expression in cancer cells with conditional medium from THP-1-differentiated macrophage culture. The change in expression of E-cadherin and Slug was abrogated when NF–κB signaling pathway was blocked. All the findings suggested that macrophages contributed to the decreased expression of E-cadherin by NF–κB/Slug pathway in hepatocellular carcinomas.