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Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma

Hideyasu Takagi1, Shigeru Sasaki, Hiromu Suzuki

  • 1First Department of Internal Medicine, Sapporo Medical University, S1, W16, Chuo-Ku, Sapporo 060-8543, Japan.

Journal of Gastroenterology
|July 2, 2008
PubMed
Abstract

Insights

Methylation and silencing of Wnt antagonist genes, such as secreted frizzled-related proteins (SFRPs), are common in hepatocellular carcinoma (HCC). This loss of function contributes to Wnt signaling activation during liver cancer development.

Area of Science:

  • Hepatocellular Carcinoma Research
  • Molecular Biology
  • Epigenetics

Background:

  • Wnt signaling pathway activation is frequent in hepatocellular carcinoma (HCC).
  • Mutations in CTNNB1, AXIN1, and AXIN2 are less common than Wnt pathway activation in HCC.

Purpose of the Study:

  • To investigate the relationship between Wnt signaling and epigenetic alterations of secreted frizzled-related protein (SFRP) genes in HCC.
  • To understand the role of SFRP gene methylation in hepatocarcinogenesis.

Main Methods:

  • Examined Wnt signaling activation via beta-catenin.
  • Assessed methylation status of SFRP family genes (SFRP1, SFRP2, SFRP4, SFRP5) in HCC cell lines and primary tumors.
  • Analyzed SFRP methylation in chronic hepatitis and liver cirrhosis.
  • Investigated the functional impact of SFRPs on Wnt signaling using gene expression and knockdown studies.

Main Results:

  • Active and nuclear beta-catenin were frequently detected in HCC cell lines.
  • Methylation of SFRP1, SFRP2, SFRP4, and SFRP5 was observed in HCC cell lines and primary HCCs.
  • SFRP methylation was also detected in chronic hepatitis and liver cirrhosis, indicating early involvement in carcinogenesis.
  • Ectopic SFRP expression suppressed Wnt signaling; SFRP1 knockdown enhanced it.

Conclusions:

  • Frequent methylation and silencing of Wnt antagonist SFRP genes occur in HCC.
  • Loss of SFRP function contributes to Wnt signaling activation during hepatocarcinogenesis.

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