Sulfatide epigenetically regulates miR-223 and promotes the migration of human hepatocellular carcinoma cells
Sulfatide epigenetically regulates miR-223 and promotes the migration of human hepatocellular carcinoma cells
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硫脂苷表观遗传调控miR-223并促进人肝细胞癌细胞的迁移
DOI：
10.1016/j.jhep.2013.12.004
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发表时间：
2014-04-01
影响因子：
25.7
通讯作者：
Wu, Xing Zhong
中科院分区：
文献类型：
--
作者：
Dong, Yi Wei;Wang, Rong;Wu, Xing Zhong
背景和目标：miR-223在人肝细胞癌（HCC）中异常表达的生物学意义和调控机制尚不清楚。我们的目的是研究miR-223在HCC中的调节。方法：在57例HCC标本中验证miR-223和整合素α V的失调。对另一组103例HCC样本进行了整合素α V和硫苷脂水平的免疫组织化学分析。表观遗传学分析用于探索硫苷脂对miR-223转录的影响。原位生长，肝内和肺转移的肿瘤来源于SMMC-7721细胞表达miR-223或糖苷磺基转移酶在mice中monitored.Results：miR-223在HCC标本和高转移细胞系中减少。增强的miR-223表达对整合素aV介导的细胞迁移具有负面影响。在原位植入模型中的转移的体内测定证明miR-223有效地抑制HCC转移。进一步的分析表明，整合素α V受miR-223负调控。此外，整合素α V亚基与103例HCC标本中高表达的硫苷脂呈显著正相关。有趣的是，肝细胞癌中的miR-223表达被硫苷脂抑制，这与乙酰化组蛋白H3和C/EBP α向前体miR-223基因启动子的募集减少有关，其中单核细胞白血病锌指（MOZ）蛋白，一种MYST型组蛋白乙酰转移酶，失去了其附着。结论：肝癌组织中miR-223表达下调与硫苷脂高表达的表观遗传调控有关，并参与肿瘤转移。(C)2013年欧洲肝脏研究协会。由Elsevier B出版。V.保留所有权利。
Background & Aims: The biological relevance and regulation mechanism of aberrant miR-223 expression in human hepatocellular carcinoma (HCC) remain unknown. Our aim was to investigate miR-223 regulation in HCC.Methods: miR-223 and integrin alpha V dysregulation were verified in 57 HCC specimens. Immunohistochemical analysis of integrin alpha V and sulfatide levels was performed on another cohort of 103 HCC samples. Epigenetic analysis was used to explore the effect of sulfatide on miR-223 transcription. Orthotopic growth, and intrahepatic and pulmonary metastasis of tumors derived from SMMC-7721 cells expressing miR-223 or cerebroside sulfotransferase were monitored in mice.Results: miR-223 was reduced in HCC specimens and highly metastatic cell lines. Enhanced miR-223 expression had a negative effect on integrin aV-mediated cell migration. In vivo assays of metastasis in an orthotopically implanted model demonstrated that miR-223 effectively inhibited HCC metastasis. Further analysis demonstrated that integrin alpha V is negatively regulated by miR-223. Moreover, the integrin alpha V subunit was significantly positively correlated with highly expressed sulfatide in 103 HCC specimens. Intriguingly, miR-223 expression was suppressed by sulfatide in HCC in association with reduced recruitment of acetylated histone H3 and C/EBP alpha to the pre-miR-223 gene promoter, where monocytic leukemia zinc finger (MOZ) protein, a MYST-type histone acetyltransferase, lost its attachment. The expression of histone deacetylases, HDAC9 and HDAC10, were greatly stimulated by sulfatide and their recruitment to miR-223 gene promoter was enhanced.Conclusions: Downregulation of miR-223 in HCC is associated with the epigenetic regulation by highly expressed sulfatide and involved in tumor metastasis. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.