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Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma
Article first published online: 22 JUN 2006
Copyright © 2006 American Cancer Society
Volume 107, Issue 3, pages 579–590, 1 August 2006
How to Cite
Shih, Y.-L., Shyu, R.-Y., Hsieh, C.-B., Lai, H.-C., Liu, K.-Y., Chu, T.-Y. and Lin, Y.-W. (2006), Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma. Cancer, 107: 579–590. doi: 10.1002/cncr.22023
- Issue published online: 18 JUL 2006
- Article first published online: 22 JUN 2006
- Manuscript Accepted: 14 MAR 2006
- Manuscript Revised: 10 MAR 2006
- Manuscript Received: 2 SEP 2005
- National Science Council, Republic of China. Grant Numbers: NSC 92-3112-B-016-006, NSC 93-3112-B-016-002, NSC 93-2311-B-016-002
- Tri-Service General Hospital, Taiwan, Republic of China. Grant Numbers: TSGH-C95-7-S01, TSGH-C95-7-S02, TSGH-C95-7-S03, TSGH-C95-7-S04
- C. Y. Chai Foundation for Advancement of Education, Sciences, and Medicine
- hepatocellular carcinoma;
- secreted frizzled-related protein 1 gene;
- promoter hypermethylation;
- loss of heterozygosity
The secreted frizzled-related protein 1 gene (SFRP1) encodes a Wnt/β-catenin signaling antagonist and frequently is inactivated by promoter methylation in many tumors. However, the role of SFRP1 in hepatocellular carcinoma (HCC) is not clear. Therefore, the authors investigated whether methylation of the SFRP1 promoter is common in HCC and whether it may influence SFRP1 expression.
Four HCC cell lines, 54 HCCs, 42 cirrhotic livers, 21 livers with chronic hepatitis, and 15 normal control tissues were analyzed for 1) SFRP1 promoter methylation by using methylation-specific polymerase chain reaction analysis and bisulfite sequencing, 2) SFRP1 messenger RNA expression by using quantitative reverse transcriptase-polymerase chain reaction analysis, and 3) loss of heterozygosity (LOH) by using microsatellite markers flanking the SFRP1 locus. HCC cells were treated with the demethylating agent 5-aza-2′-deoxycytidine to determine whether it could restore SFRP1 expression.
SFRP1 promoter methylation was observed in 75%, 48.2%, 21.4%, 14.3% and 0% in HCC cell lines, primary HCCs, cirrhotic livers, livers with chronic hepatitis, and normal control tissues, respectively. Methylation of the SFRP1 promoter region in HCCs increased significantly compared with control tissues. All samples with SFRP1 methylation showed down-regulation of SFRP1 expression. Demethylation treatment with 5-aza-2′-deoxycytidine in HCC cells restored SFRP1 expression. Moreover, LOH of markers D8S505 and D8S1722 was found in 25% and 27.6% of the informative samples, respectively.
The current results suggested that promoter hypermethylation of SFRP1 is a common event in HCC and plays an important role in the regulation of SFRP1 expression. In addition to methylation-mediated down-regulation of SFRP1, LOH also may play a role. Cancer 2006. © 2006 American Cancer Society.