This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, C.-H. Articles by Liaw, Y.-F. Search for Related Content PubMed PubMed Citation Articles by Lin, C.-H. Articles by Liaw, Y.-F.

Genome-wide Hypomethylation in Hepatocellular Carcinogenesis¹

Liver Research Unit [S-Y. H., I-S. S., W-C. S., Y-F. L.], Departments of General Surgery [W-C. L.], and Pathology [T-C. C.], Chang Gung Memorial Hospital, Taipei, Taiwan 155, and Department of Microbiology and Immunology, Chang Gung University School of Medicine, Taoyuan 333 [C-H. L., S-Y. H.], Republic of Taiwan

Aberrant genome-wide hypomethylation has been thought to be related to tumorigenesis. However, its mechanism and implications in hepatocellular carcinogenesis remain to be elucidated. Samples of hepatoma (hepatocellular carcinoma, HCC) and paired non-HCC liver tissues were obtained from 17 HCC patients. Normal liver tissues obtained from three individuals were used as controls. Compared with the paired non-HCC liver tissues, genome-wide 5-methylcytosine content in HCC was reduced in all of the tested HCC samples (P < 0.001). Conversely, genome-wide 5-methylcytosine content did not significantly differ among normal, noncirrhotic, and cirrhotic liver tissues. Moreover, the degree of reduced DNA methylation was related to late histopathological HCC grade (P = 0.005) and large tumor size (P = 0.079). Compared with the paired non-HCC liver tissues, expression of DNA methyltransferases DNMT-1, DNMT-3A, and DNMT-3B and the DNA methyltransferase-like gene, DNMT-2, was up-regulated in 53, 41, 59, and 47% of the HCC samples, respectively. Surprisingly, small amounts of LINE-1 retrotransposon transcripts were detected in HCC and non-HCC as well as normal liver tissues, and the expression levels were not significantly different in HCC compared with the paired non-HCC or normal liver tissues. Of interest, the 3' ends of these LINE-1 transcripts were truncated. Our findings suggest that genome-wide hypomethylation in HCC is a continuing process that persists throughout the lifetime of the tumor cells rather than a historical event occurring in precancer stages or in cell origins for HCC. Up-regulation of DNA methyltransferases might simply be a result of increased cell proliferation in cancer. In addition, our results did not support the hypothesis of activation of transposable elements in HCC via genome-wide hypomethylation.

This article has been cited by other articles:

				H. S. Lee, B.-H. Kim, N.-Y. Cho, E. J. Yoo, M. Choi, S.-H. Shin, J.-J. Jang, K.-S. Suh, Y. S. Kim, and G. H. Kang Prognostic Implications of and Relationship Between CpG Island Hypermethylation and Repetitive DNA Hypomethylation in Hepatocellular Carcinoma Clin. Cancer Res., February 1, 2009; 15(3): 812 - 820. [Abstract] [Full Text] [PDF]

				W. Gao, Y. Kondo, L. Shen, Y. Shimizu, T. Sano, K. Yamao, A. Natsume, Y. Goto, M. Ito, H. Murakami, et al. Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas Carcinogenesis, October 1, 2008; 29(10): 1901 - 1910. [Abstract] [Full Text] [PDF]

				C. S. Furniss, C. J. Marsit, E. A. Houseman, K. Eddy, and K. T. Kelsey Line Region Hypomethylation Is Associated with Lifestyle and Differs by Human Papillomavirus Status in Head and Neck Squamous Cell Carcinomas Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 966 - 971. [Abstract] [Full Text] [PDF]

				I. Teneng, V. Stribinskis, and K. S. Ramos Context-specific regulation of LINE-1 Genes Cells, October 1, 2007; 12(10): 1101 - 1110. [Abstract] [Full Text] [PDF]

				N. Widodo, C. C. Deocaris, K. Kaur, K. Hasan, T. Yaguchi, K. Yamasaki, T. Sugihara, T. Ishii, R. Wadhwa, and S. C. Kaul Stress Chaperones, Mortalin, and Pex19p Mediate 5-Aza-2' Deoxycytidine-Induced Senescence of Cancer Cells by DNA Methylation-Independent Pathway J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2007; 62(3): 246 - 255. [Abstract] [Full Text] [PDF]

				S. H. Tang, D. H. Yang, W. Huang, H. K. Zhou, X. H. Lu, and G. Ye Hypomethylated P4 Promoter Induces Expression of the Insulin-Like Growth Factor-II Gene in Hepatocellular Carcinoma in a Chinese Population. Clin. Cancer Res., July 15, 2006; 12(14): 4171 - 4177. [Abstract] [Full Text] [PDF]

				A. Loriot, E. De Plaen, T. Boon, and C. De Smet Transient Down-regulation of DNMT1 Methyltransferase Leads to Activation and Stable Hypomethylation of MAGE-A1 in Melanoma Cells J. Biol. Chem., April 14, 2006; 281(15): 10118 - 10126. [Abstract] [Full Text] [PDF]

				Y. Yamada, L. Jackson-Grusby, H. Linhart, A. Meissner, A. Eden, H. Lin, and R. Jaenisch Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis PNAS, September 20, 2005; 102(38): 13580 - 13585. [Abstract] [Full Text] [PDF]

				P. M. Das and R. Singal DNA Methylation and Cancer J. Clin. Oncol., November 15, 2004; 22(22): 4632 - 4642. [Abstract] [Full Text] [PDF]

				R. Saffroy, P. Pham, F. Chiappini, M. Gross-Goupil, L. Castera, D. Azoulay, A. Barrier, D. Samuel, B. Debuire, and A. Lemoine The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis Carcinogenesis, August 1, 2004; 25(8): 1443 - 1448. [Abstract] [Full Text] [PDF]

				N. Yanagawa, G. Tamura, T. Honda, M. Endoh, S. Nishizuka, and T. Motoyama Demethylation of the Synuclein {gamma} Gene CpG Island in Primary Gastric Cancers and Gastric Cancer Cell Lines Clin. Cancer Res., April 1, 2004; 10(7): 2447 - 2451. [Abstract] [Full Text] [PDF]

				K. Ghoshal, S. Majumder, J. Datta, T. Motiwala, S. Bai, S. M. Sharma, W. Frankel, and S. T. Jacob Role of Human Ribosomal RNA (rRNA) Promoter Methylation and of Methyl-CpG-binding Protein MBD2 in the Suppression of rRNA Gene Expression J. Biol. Chem., February 20, 2004; 279(8): 6783 - 6793. [Abstract] [Full Text] [PDF]

				N. Sato, A. Maitra, N. Fukushima, N. T. van Heek, H. Matsubayashi, C. A. Iacobuzio-Donahue, C. Rosty, and M. Goggins Frequent Hypomethylation of Multiple Genes Overexpressed in Pancreatic Ductal Adenocarcinoma Cancer Res., July 15, 2003; 63(14): 4158 - 4166. [Abstract] [Full Text] [PDF]

				R. E. Watson and J. I. Goodman Effects of Phenobarbital on DNA Methylation in GC-Rich Regions of Hepatic DNA from Mice That Exhibit Different Levels of Susceptibility to Liver Tumorigenesis Toxicol. Sci., July 1, 2002; 68(1): 51 - 58. [Abstract] [Full Text] [PDF]