MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors.
MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors.
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DOI：
10.1002/hep.27816
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Barry CT
中科院分区：
文献类型：
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作者：
Chuang KH;Whitney-Miller CL;Chu CY;Zhou Z;Dokus MK;Schmit S;Barry CT
血管侵犯为肿瘤转移提供了直接途径。 microRNA (miRNA) 表达在肿瘤血管侵袭中发挥作用的程度尚不清楚。在这里，我们报告说，miR-494 在具有血管侵袭的人肝细胞癌 (HCC) 肿瘤中表达上调，并且可以通过多种侵袭抑制 miRNA 的基因失活来促进 HCC 细胞侵袭。我们的结果表明，111 易位 (TET) 甲基胞嘧啶双加氧酶（主要是 HCC 细胞中的 TET1）是 miR-494 的直接靶标。在多个侵袭抑制 miRNA 基因的近端胞嘧啶-磷酸-鸟嘌呤 (CpG) 区域中观察到的 5'-羟甲基胞嘧啶水平降低与其在 miR-494 过表达时的转录抑制密切相关，而强制 DNA 去甲基化可以消除这种抑制。此外，TET1 敲低显示出与 miR-494 过表达相似的效果。相反，抑制 miR-494 或强制 TET1 表达能够恢复侵袭抑制 miRNA 并抑制 miR-494 介导的 HCC 细胞侵袭。结论：miR-494可以通过直接靶向TET1抑制基因组DNA去甲基化来触发多种侵袭抑制miRNA的基因沉默，从而导致肿瘤血管侵袭。 （肝病学 2015 年；62：466–480
Vascular invasion provides a direct route for tumor metastasis. The degree to which microRNA (miRNA) expression plays a role in tumor vascular invasion is unclear. Here, we report that miR-494 is up-regulated in human hepatocellular carcinoma (HCC) tumors with vascular invasion and can promote HCC cell invasiveness by gene inactivation of multiple invasion-suppressor miRNAs. Our results show that ten eleven translocation (TET) methylcytosine dioxygenase, predominantly TET1 in HCC cells, is a direct target of miR-494. The reduced 5′-hydroxymethylcytosine levels observed in the proximal cytosine-phosphate-guanine (CpG) regions of multiple invasion-suppressor miRNA genes are strongly associated with their transcriptional repression upon miR-494 overexpression, whereas enforced DNA demethylation can abolish the repression. Furthermore, TET1 knockdown shows a similar effect as miR-494 overexpression. Conversely, miR-494 inhibition or enforced TET1 expression is able to restore invasion-suppressor miRNAs and inhibit miR-494-mediated HCC cell invasion. Conclusions: miR-494 can trigger gene silencing of multiple invasion-suppressor miRNAs by inhibiting genomic DNA demethylation by direct targeting of TET1, thereby leading to tumor vascular invasion. (Hepatology 2015;62:466–480