Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcinoma.
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.
Huang
Jian
J
Shanghai-Ministry Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China.
Zhang
Xin
X
Zhang
Min
M
Zhu
Jing-De
JD
Zhang
Yun-Li
YL
Lin
Yun
Y
Wang
Ke-Sheng
KS
Qi
Xiao-Fei
XF
Zhang
Qin
Q
Liu
Guang-Zhen
GZ
Yu
Jian
J
Cui
Ying
Y
Yang
Peng-Yuan
PY
Wang
Zhi-Qin
ZQ
Han
Ze-Guang
ZG
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
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000509:alpha-Fetoproteins