Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma
Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma
复制标题
MiR-200 家族的表观遗传激活有助于 H19 介导的肝细胞癌转移抑制。
DOI：
10.1093/carcin/bgs381
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发表时间：
2013-03-01
期刊：
影响因子：
4.7
通讯作者：
Sun, Shu-han
中科院分区：
文献类型：
--
作者：
Zhang, Ling;Yang, Fu;Sun, Shu-han
尽管在哺乳动物中已经鉴定出许多长链非编码RNA（lncRNA），但它们的许多生物学作用仍有待于表征。早期的报告表明，H19有助于致癌，包括肝细胞癌（HCC）。对Oncomine资源的检查显示，大多数HCC病例以与肝脏相当的水平表达H19，具有较低表达的趋势。这与我们之前的微阵列数据一致，表明H19在HCC中的作用更复杂，需要进行表征。在这项研究中，H19的表达水平在HCC患者的肝脏样品的不同区域进行了评估。在肝癌细胞系SMMC 7721和HCCLM 3中对这种lncRNA进行功能丧失和获得研究，以表征其对基因表达的影响，并评估其对体外和体内肝癌转移的影响。在这项研究中，我们发现H19在肿瘤内HCC组织（T）中的表达低于肿瘤周围组织（L）。此外，低T/L比值的H19预测预后不良。H19抑制HCC进展转移和上皮-间质转化标志物的表达。此外，H19与蛋白复合物hnRNP U/PCAF/RNAPol II结合，通过增加组蛋白乙酰化激活miR-200家族。结果表明，H19可以改变miR-200通路，从而有助于间充质向上皮的转变和抑制肿瘤转移。这些数据为迄今为止关于H19与癌症之间关系的令人困惑的文献提供了解释，并可能表明靶向H19和miR-200家族的联合疗法的发展。
Although numerous long non-coding RNAs (lncRNAs) have been identified in mammals, many of their biological roles remain to be characterized. Early reports suggest that H19 contributes to carcinogenesis, including hepatocellular carcinoma (HCC). Examination of the Oncomine resource showed that most HCC cases express H19 at a level that is comparable with the liver, with a tendency toward lower expression. This is consistent with our previous microarray data and indicates a more complicated role of H19 in HCC that needs to be characterized. In this study, the expression level of H19 was assessed in different regions of HCC patients' liver samples. Loss- and gain-of-function studies on this lncRNA in the HCC cell lines, SMMC7721 and HCCLM3, were used to characterize its effects on gene expression and to assess its effect on HCC metastasis both in vitro and in vivo. In this study, we show that H19 was underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L). Additionally, low T/L ratio of H19 predicted poor prognosis. H19 suppressed HCC progression metastasis and the expression of markers of epithelial-to-mesenchymal transition. Furthermore, H19 associated with the protein complex hnRNP U/PCAF/RNAPol II, activating miR-200 family by increasing histone acetylation. The results demonstrate that H19 can alter the miR-200 pathway, thus contributing to mesenchymal-to-epithelial transition and to the suppression of tumor metastasis. These data provide an explanation for the hitherto puzzling literature on the relationship between H19 and cancer, and could suggest the development of combination therapies that target H19 and the miR-200 family.