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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
Author(s) -
Chuang KuangHsiang,
WhitneyMiller Christa L.,
Chu ChinYi,
Zhou Zhongren,
Dokus M. Katherine,
Schmit Shan,
Barry Christopher T.
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27816
Subject(s) - microrna , biology , cancer research , gene knockdown , gene silencing , suppressor , tumor suppressor gene , oncomir , epigenetics , dna methylation , dna demethylation , cpg site , carcinogenesis , microbiology and biotechnology , gene , gene expression , genetics
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. (H epatology 2015;62:466–480