title: Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcinoma.
abstract: Dysregulation of a genomic imprinting gene can contribute to carcinogenesis. Here, delta-like 1 homolog (Drosophila) (DLK1), a paternally expressed gene, was found to be significantly up-regulated in 60 (73.2%) of a total of 82 hepatocellular carcinoma (HCC) specimens using reverse transcription-polymerase chain reaction. In addition, immunohistochemistry staining was performed in another 88 HCC specimens, of which 50 (56.8%) cancerous tissues were considered as positive. The expression of DLK1 was obviously induced in HCC cells, Bel-7402 and MHCC-H, by a demethylation agent, 5-aza-2'-deoxycytidine. Furthermore, both demethylation of the DLK1 promoter (-565 to -362) and hypermethylation of the imprinting control domain in the region upstream of maternally expressed gene 3 were identified in a few HCC specimens. This implies that deregulation of genomic DNA methylation of the imprinted domain could be attributed to the up-regulation of DLK1 in HCC, although the undoubtedly complex mechanisms involved in the epigenetic event should be further investigated in HCC. Surprisingly, the expression of DLK1 in HCC was confirmed to be monoallelic specific, not biallelic, in three HCC specimens with a single nucleotide polymorphism as at T852C (rs2295660). Importantly, the exogenous DLK1 can significantly promote the cell proliferation of SMMC-7721 cells, a HCC cell line, whereas the suppression of endogenetic DLK1 through RNA interference can markedly inhibit cell growth, colony formation and tumorigenicity of HepG2, Hep3B and HuH-7 cells. These data suggest that DLK1 as an imprinted gene could be significantly up-regulated in HCC due to certain epigenetic events and contribute to the oncogenesis of this tumor.
authors.affiliation: Shanghai-Ministry Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jing-De
authors.initials: JD
authors.lastname: Zhu
authors.forename: Yun-Li
authors.initials: YL
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.forename: Ke-Sheng
authors.initials: KS
authors.lastname: Wang
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Qi
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Guang-Zhen
authors.initials: GZ
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Yang
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Ze-Guang
authors.initials: ZG
authors.lastname: Han
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000509:alpha-Fetoproteins