title: miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A.
abstract: The hepatitis B virus x (HBx) protein has been implicated in HBV-related hepatocellular carcinoma (HCC) pathogenesis. However, whether HBx regulates miRNA expression that plays important roles in gene regulation during hepatocarcinogenesis remains unknown. The expression of microRNA-101 (miR-101) in HBV-related HCC tissues and HCC cells was evaluated by real-time PCR. The direct target of miR-101, DNA methyltransferase 3A (DNMT3A), was identified in silico and validated using a 3'-UTR reporter assay. miR-101 was functionally characterized in cells with transiently altered miR-101 expression. HBx expression was found to have a significant inverse correlation with miR-101 expression in HBx-expressing HepG2 compared to control HepG2 cells. miR-101 expression was frequently down-regulated in HBV-related HCC tissues compared to adjacent noncancerous hepatic tissues and had a significant inverse correlation with DNMT3A expression in HBV-related HCCs. Further characterization of miR-101 revealed that it negatively regulated DNA methylation partly through targeting DNMT3A. HBx-mediated miR-101 down-regulation and DNMT3A up-regulation supported the enhanced DNA methylation of several tumor-suppressor genes in HBx-expressing cells. Our studies demonstrating the deregulation of miR-101 expression by HBx may provide novel mechanistic insights into HBV-mediated hepatocarcinogenesis and identify a potential miRNA-based targeted approach for treating HBV-related HCC.
authors.affiliation: Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xufu
authors.initials: X
authors.lastname: Wei
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.forename: Guosheng
authors.initials: G
authors.lastname: Ren
authors.forename: Cui
authors.initials: C
authors.lastname: Tan
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D005260:Female; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C000717967:DNMT3A protein, human; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A