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Carcinogenesis Advance Access published online on November 17, 2006
Carcinogenesis, doi:10.1093/carcin/bgl215
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 14, 2006
Revised October 31, 2006
Accepted November 2, 2006

CARCINOGENESIS

Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcinoma

Jian Huang 1 {dagger}, Xin Zhang 2 {dagger}, Min Zhang 2 {dagger}, Jing-De Zhu 3 {dagger}, Yun-Li Zhang 2, Yun Lin 2, Ke-Sheng Wang 2, Xiao-Fei Qi 2, Qin Zhang 2, Guang-Zhen Liu 4, Jian Yu 3, Ying Cui 5, Peng-Yuan Yang 6, Zhi-Qin Wang 2, and Ze-Guang Han 2 *

1 Shanghai-Ministry Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China; Department of chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
2 Shanghai-Ministry Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China
3 The State-Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, LN 2200/25, Xietu Road, Shanghai 200032, China
4 Department of Pathology, The First Affiated Hospital of Xuzhou Medical College, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China
5 Affiated Cancer Hospital of Guangxi Medical College, 71 Heti Road, Nanning, Guangxi, 530021, China
6 Department of chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China

* To whom correspondence should be addressed.
Ze-Guang Han, E-mail: hanzg{at}chgc.sh.cn


  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-PCR. In addition, immunohistochemistry staining was performed in another 88 HCC specimens, of which 50/88 (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 (DAC). Furthermore, both demethylation of the DLK1 promoter (-565 ~ -362) and hypermethylation of the imprinting control domain in the region upstream of maternally expressed gene 3 (MEG3) 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 bi-allelic, 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.

Keywords: DLK1; hepatocellular carcinoma; DNA methylation; RNA interference; hepatocarcinogenesis.

{dagger}These authors contributed equally to this work.


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