SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway

<jats:title>Abstract</jats:title><jats:p>Oncogenic activation of the Wnt/β‐catenin signaling pathway is common in hepatocellular carcinoma (HCC). The secreted frizzled‐related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications for carcinogenesis. Promoter hypermethylation of <jats:italic>SFRP</jats:italic> genes is common in human cancers. However, the role of <jats:italic>SFRPs</jats:italic> in HCC is not clear. Recently, we have shown that <jats:italic>SFRP1</jats:italic> is frequently downregulated through promoter hypermethylation. To confirm and extend these findings, the methylation status of the other <jats:italic>SFRP</jats:italic> members, including <jats:italic>SFRP2</jats:italic>, <jats:italic>SFRP4</jats:italic> and <jats:italic>SFRP5,</jats:italic> was examined by methylation‐specific polymerase chain reaction (MS‐PCR). Hypermethylation of <jats:italic>SFRP</jats:italic> genes, except for <jats:italic>SFRP4,</jats:italic> is frequent in HCCs and the levels found here were significantly higher than those seen in cirrhotic livers, chronic hepatitis livers and normal controls (<jats:italic>p</jats:italic> < 0.0001 for <jats:italic>SFRP1</jats:italic> and <jats:italic>SFRP2, p</jats:italic> < 0.05 for <jats:italic>SFRP5</jats:italic>). To investigate the role of <jats:italic>SFRP1</jats:italic> in HCCs, we used re‐expression of <jats:italic>SFRP1</jats:italic> in β‐catenin‐dependent HCC cell lines: Huh6 and HepG2. Restoration of <jats:italic>SFRP1</jats:italic> attenuated Wnt signaling in those Huh6 hepatoma cells with a β‐catenin gene point mutation, decreased abnormal accumulation of β‐catenin in the nucleus and suppressed cell growth. Conversely, restoration of <jats:italic>SFRP1</jats:italic> in HepG2 hepatoma cells with truncated β‐catenin could not block the Wnt signaling pathway. Furthermore, knocking down <jats:italic>SFRP1</jats:italic> by RNA interference in β‐catenin‐deficient cell lines (SK‐Hep1) stimulated Wnt signaling and promoted cell growth. Our data suggested that <jats:italic>SFRP1</jats:italic> suppressed liver cancer cells growth through Wnt canonical signaling. Moreover, β‐catenin‐independent noncanonical pathway might be involved in Wnt signaling activation through unknown molecules in HCC. © 2007 Wiley‐Liss, Inc.</jats:p>