title: 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.
  
  
  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.
authors.affiliation: The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.|Department of Surgery Research, University of Rochester Medical Center, Rochester, NY.|Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY.
authors.forename: Kuang-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
authors.forename: Christa L
authors.initials: CL
authors.lastname: Whitney-Miller
authors.affiliation: Division of Neonatology and Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY.|Pediatric Molecular and Personalized Medicine Program, University of Rochester Medical Center, Rochester, NY.
authors.forename: Chin-Yi
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Surgery Research, University of Rochester Medical Center, Rochester, NY.
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Dokus
authors.affiliation: Department of Surgery Research, University of Rochester Medical Center, Rochester, NY.
authors.forename: Shannon
authors.initials: S
authors.lastname: Schmit
authors.affiliation: The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.|Department of Surgery Research, University of Rochester Medical Center, Rochester, NY.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Barry
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056945:Hep G2 Cells / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D006899:Mixed Function Oxygenases; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D014178:Translocation, Genetic / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C547168:MIRN494 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human
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