title: Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma.
abstract: Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Maya A
authors.initials: MA
authors.lastname: Kappil
authors.forename: Hui
authors.initials: H
authors.lastname: Chen Wu
authors.forename: Muhammad G
authors.initials: MG
authors.lastname: Kibriya
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.forename: Farzana
authors.initials: F
authors.lastname: Jasmine
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: Ming-Whei
authors.initials: MW
authors.lastname: Yu
authors.forename: Chien-Jen
authors.initials: CJ
authors.lastname: Chen
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D015894:Genome, Human; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism
chemical_list: C547183:MIRN10 microRNA, human; C542543:MIRN196 microRNA, human; D035683:MicroRNAs