Secreted Frizzled-Related Protein 4 Is Silenced by Hypermethylation and Induces Apoptosis in β-Catenin–Deficient Human Mesothelioma Cells

Cancer Research - Tập 65 Số 3 - Trang 743-748 - 2005
Biao He1, Amie Y. Lee1, Sina Dadfarmay1, Liang You1, Zhidong Xu1, Noemı́ Reguart1,2, Julien Mazières1,3, Iwao Mikami1, Frank McCormick1, David M. Jablons1
11Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, California;
22Medical Oncology Service, Institut Catalàd'Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain; and
33Department Innovation Therapeutique et Oncologie Moleculaire, Institut National de la Sante et de la Recherche Medicale U563, Institut Claudius Regaud, Toulouse, France

Tóm tắt

Abstract The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications in tumorigenesis. Frequent promoter hypermethylation of SFRPs has been identified in human cancer. Restoration of SFRP function attenuates Wnt signaling and induces apoptosis in a variety of cancer types. Wnt signaling is known to inhibit apoptosis through activation of β-catenin/Tcf–mediated transcription. Recently, we identified aberrant Wnt activation as a result of Dishevelled overexpression in malignant mesothelioma. Here, we report that silencing of SFRP4 is correlated with promoter hypermethylation in β-catenin–deficient mesothelioma cell lines. Reexpression of SFRP4 in these β-catenin–deficient mesothelioma cell lines blocks Wnt signaling, induces apoptosis, and suppresses growth. Conversely, knocking down SFRP4 by small interfering RNA in cell lines expressing both SFRP4 and β-catenin stimulates Wnt signaling, promotes cell growth, and inhibits chemodrug-induced apoptosis. Our results suggest that methylation silencing of SFRP4 may play an important role in aberrant Wnt activation in mesothelioma even in the absence of β-catenin. Our data also suggest that β-catenin–independent noncanonical pathway(s) may be involved in the apoptotic inhibition caused by activation of Wnt signaling.

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Cancer Research

Tập 65 Số 3

743-748

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