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MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors.


ABSTRACT: 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.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.

SUBMITTER: Chuang KH 

PROVIDER: S-EPMC4682466 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors.

Chuang Kuang-Hsiang KH   Whitney-Miller Christa L CL   Chu Chin-Yi CY   Zhou Zhongren Z   Dokus M Katherine MK   Schmit Shannon S   Barry Christopher T CT  

Hepatology (Baltimore, Md.) 20150506 2


<h4>Unlabelled</h4>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  ...[more]

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