This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Zhong, S. Articles by Johnson, P. J. Search for Related Content PubMed PubMed Citation Articles by Zhong, S. Articles by Johnson, P. J.

Silencing of GSTP1 Gene by CpG Island DNA Hypermethylation in HBV-associated Hepatocellular Carcinomas¹

Departments of Clinical Oncology [S. Z., M. W. T., W. Y., C. L., P. J. J.] and Chemical Pathology [Y. M. D. L.], Sir Y. K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N. T., Hong Kong SAR, China

Purpose and Experimental Design: Glutathione S-transferases, enzymes that defend cells against damage mediated by oxidant and electrophilic carcinogens, may be critical determinants of cancer pathogenesis. In this report, we assess the role of epigenetic silencing of the GSTP1 gene, a gene encoding the -class glutathione S-transferase, in the pathogenesis of hepatitis B virus (HBV)-associated hepatocellular carcinomas (HCC). The cell lines Hep3B, HepG2, and a cohort of 43 HBV-associated HCC tissue specimens and corresponding nontumor tissues were subjected to analysis for GSTP1 epigenetic alteration and expression. GSTP1 "CpG" island DNA hypermethylation in the liver cell lines, and the tissue specimens were determined by methylation-specific PCR and correlated with expression of the gene using reverse-transcription PCR, immunoblotting, and immunohistochemistry.

Results: GSTP1 CpG island DNA hypermethylation was detected in 28 of 43 (65.1%) HCC tissues and 4 of 40 (10%) corresponding nontumor tissues. GSTP1 protein was absent in those cases showing hypermethylation of the gene. Similarly, DNA from Hep3B and HepG2 cell lines displayed complete GSTP1 hypermethylation in the CpG island, and they failed to express GSTP1 mRNA and the corresponding protein product. Treatment of the cell lines with the DNA methyltransferase inhibitor 5-aza-deoxycytidine reversed the hypermethylation, and restored GSTP1 mRNA and polypeptide expression.

Conclusions: These data indicate that epigenetic silencing of GSTP1 gene expression by CpG island DNA hypermethylation is common in human HBV-associated HCC. In addition, somatic GSTP1 inactivation via CpG island hypermethylation may contribute to the pathogenesis of this malignancy.

This article has been cited by other articles:

				B. Lu, Y. Ma, G. Wu, X. Tong, H. Guo, A. Liang, W. Cong, C. Liu, H. Wang, M. Wu, et al. Methylation of Tip30 Promoter Is Associated with Poor Prognosis in Human Hepatocellular Carcinoma Clin. Cancer Res., November 15, 2008; 14(22): 7405 - 7412. [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]

				E. Ko, Y. Kim, S.-J. Kim, J.-W. Joh, S. Song, C.-K. Park, J. Park, and D.-H. Kim Promoter Hypermethylation of the p16 Gene Is Associated with Poor Prognosis in Recurrent Early-Stage Hepatocellular Carcinoma Cancer Epidemiol. Biomarkers Prev., September 1, 2008; 17(9): 2260 - 2267. [Abstract] [Full Text] [PDF]

				A. M. Moyer, O. E. Salavaggione, T.-Y. Wu, I. Moon, B. W. Eckloff, M. A.T. Hildebrandt, D. J. Schaid, E. D. Wieben, and R. M. Weinshilboum Glutathione S-Transferase P1: Gene Sequence Variation and Functional Genomic Studies Cancer Res., June 15, 2008; 68(12): 4791 - 4801. [Abstract] [Full Text] [PDF]

				M. Tada, F. Kanai, Y. Tanaka, K. Tateishi, M. Ohta, Y. Asaoka, M. Seto, R. Muroyama, K. Fukai, F. Imazeki, et al. Down-Regulation of Hedgehog-Interacting Protein through Genetic and Epigenetic Alterations in Human Hepatocellular Carcinoma Clin. Cancer Res., June 15, 2008; 14(12): 3768 - 3776. [Abstract] [Full Text] [PDF]

				E. Dejeux, V. Audard, C. Cavard, I. G. Gut, B. Terris, and J. Tost Rapid Identification of Promoter Hypermethylation in Hepatocellular Carcinoma by Pyrosequencing of Etiologically Homogeneous Sample Pools J. Mol. Diagn., September 1, 2007; 9(4): 510 - 520. [Abstract] [Full Text] [PDF]

				J. K. Jung, P. Arora, J. S. Pagano, and K. L. Jang Expression of DNA Methyltransferase 1 Is Activated by Hepatitis B Virus X Protein via a Regulatory Circuit Involving the p16INK4a-Cyclin D1-CDK 4/6-pRb-E2F1 Pathway Cancer Res., June 15, 2007; 67(12): 5771 - 5778. [Abstract] [Full Text] [PDF]

				N. Nishida, T. Nishimura, T. Nagasaka, I. Ikai, G. Ajay, and C. R. Boland Extensive Methylation Is Associated with {beta}-Catenin Mutations in Hepatocellular Carcinoma: Evidence for Two Distinct Pathways of Human Hepatocarcinogenesis Cancer Res., May 15, 2007; 67(10): 4586 - 4594. [Abstract] [Full Text] [PDF]

				Y.-J. Zhang, H.-C. Wu, J. Shen, H. Ahsan, W. Y. Tsai, H.-I Yang, L.-Y. Wang, S.-Y. Chen, C.-J. Chen, and R. M. Santella Predicting Hepatocellular Carcinoma by Detection of Aberrant Promoter Methylation in Serum DNA Clin. Cancer Res., April 15, 2007; 13(8): 2378 - 2384. [Abstract] [Full Text] [PDF]

				S.-Y. Kuang, P. E. Jackson, J.-B. Wang, P.-X. Lu, A. Munoz, G.-S. Qian, T. W. Kensler, and J. D. Groopman Specific mutations of hepatitis B virus in plasma predict liver cancer development PNAS, March 9, 2004; 101(10): 3575 - 3580. [Abstract] [Full Text] [PDF]

				P. E. Jackson, S.-Y. Kuang, J.-B. Wang, P. T. Strickland, A. Munoz, T. W. Kensler, G.-S. Qian, and J. D. Groopman Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients Carcinogenesis, October 1, 2003; 24(10): 1657 - 1663. [Abstract] [Full Text] [PDF]

				S. Zhong, W. Yeo, M. W. Tang, N. Wong, P. B. S. Lai, and P. J. Johnson Intensive Hypermethylation of the CpG Island of Ras Association Domain Family 1A in Hepatitis B Virus-associated Hepatocellular Carcinomas Clin. Cancer Res., August 1, 2003; 9(9): 3376 - 3382. [Abstract] [Full Text] [PDF]