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SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway
Author(s) -
Shih YuLueng,
Hsieh ChungBao,
Lai HungCheng,
Yan MingDe,
Hsieh TsaiYuan,
Chao YouChen,
Lin YaWen
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22750
Subject(s) - wnt signaling pathway , hccs , lrp5 , biology , frizzled , lrp6 , cancer research , carcinogenesis , signal transduction , dna methylation , cell growth , epigenetics , methylation , microbiology and biotechnology , cancer , gene , genetics , gene expression , hepatocellular carcinoma
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 SFRP genes is common in human cancers. However, the role of SFRPs in HCC is not clear. Recently, we have shown that SFRP1 is frequently downregulated through promoter hypermethylation. To confirm and extend these findings, the methylation status of the other SFRP members, including SFRP2 , SFRP4 and SFRP5, was examined by methylation‐specific polymerase chain reaction (MS‐PCR). Hypermethylation of SFRP genes, except for SFRP4, is frequent in HCCs and the levels found here were significantly higher than those seen in cirrhotic livers, chronic hepatitis livers and normal controls ( p < 0.0001 for SFRP1 and SFRP2, p < 0.05 for SFRP5 ). To investigate the role of SFRP1 in HCCs, we used re‐expression of SFRP1 in β‐catenin‐dependent HCC cell lines: Huh6 and HepG2. Restoration of SFRP1 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 SFRP1 in HepG2 hepatoma cells with truncated β‐catenin could not block the Wnt signaling pathway. Furthermore, knocking down SFRP1 by RNA interference in β‐catenin‐deficient cell lines (SK‐Hep1) stimulated Wnt signaling and promoted cell growth. Our data suggested that SFRP1 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.