NDLI: Epigenetic silencing of sFRP1 activates the canonical Wnt pathway and contributes to increased cell growth and proliferation in hepatocellular carcinoma

Content Provider	Springer Nature Link
Author	Kaur, Pushpinder Mani, Samson Cros, Marie Pierre Scoazec, Jean Yves Chemin, Isabelle Hainaut, Pierre Herceg, Zdenko
Copyright Year	2012
Abstract	The Wnt pathway is a key regulator of embryonic development and stem cells, and its aberrant activation is associated with human malignancies, most notably hepatocellular carcinoma (HCC). Epigenetic deregulation of the genes encoding the secreted frizzled-related proteins (sFRPs), the Wnt signalling antagonists, has been linked with aberrant hyperactivation of the Wnt signalling in HCC cells; however, the precise underlying mechanism remains elusive. We investigated the methylation profiles of Wnt antagonists in liver samples of different stages of HCC development and liver cancer cell lines and studied the functional impact of aberrant epigenetic silencing of sFRPs on the canonical Wnt pathway and cell viability. We found that the sFRP1 gene encoding the subunit is a frequent target of aberrant DNA hypermethylation and silencing in HCC tumours, whereas other extracellular Wnt antagonists, WIF1 and Dkk3, exhibited no methylation in tumour cells, consistent with the notion that aberrant methylation events in cancer cells are non-randomly distributed among the genes and that there is a strong preference for hypermethylation of specific genes in HCC. In addition, by comparing sFRP1 methylation status in HCC tumours with normal, cirrhotic and chronic hepatitis liver tissues, we identified sFRP1 gene as a potential early marker of HCC. The restoration of sFRP1 expression in cancer cells by ectopic expression inhibited Wnt activity accompanied with destabilization of β-catenin and downregulation of c-Myc and cyclin D1, the known downstream targets of Wnt pathway. Importantly, restoring sFRP1 levels in cancer cells inhibited cell growth and induced apoptotic cell death. This study supports the critical role for sFRP1 silencing in hepatocellular carcinoma and reinforces the importance of the Wnt antagonists in preventing oncogenic stabilization of β-catenin and chronic activation of the canonical Wnt pathway, suggesting that sFRP1 may be an attractive target for early cancer detection and therapeutic intervention.
Starting Page	325
Ending Page	336
Page Count	12
File Format	PDF
ISSN	10104283
Journal	Tumor Biology
Volume Number	33
Issue Number	2
e-ISSN	14230380
Language	English
Publisher	Springer Netherlands
Publisher Date	2012-02-15
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	DNA methylation Hepatocellular carcinoma sFRP1 Canonical Wnt pathway Wnt signalling antagonists Epigenetic silencing Early biomarker Cancer Research
Content Type	Text
Resource Type	Article
Subject	Medicine Cancer Research

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