This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by He, B. Articles by Jablons, D. M. Search for Related Content PubMed PubMed Citation Articles by He, B. Articles by Jablons, D. M.

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

¹ Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, California; ² Medical Oncology Service, Institut Catalàd'Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain; and ³ Department Innovation Therapeutique et Oncologie Moleculaire, Institut National de la Sante et de la Recherche Medicale U563, Institut Claudius Regaud, Toulouse, France

Requests for reprints: David M. Jablons, Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, 1600 Divisadero Street, C322C, Campus Box 1674, San Francisco, CA 94115. Phone: 415-353-7502; Fax: 415-502-3179; E-mail: jablonsd{at}surgery.ucsf.edu.

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 ß-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 ß-catenin–deficient mesothelioma cell lines. Reexpression of SFRP4 in these ß-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 ß-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 ß-catenin. Our data also suggest that ß-catenin–independent noncanonical pathway(s) may be involved in the apoptotic inhibition caused by activation of Wnt signaling.

Key Words: human • mesothelioma • methylation • apoptosis • Wnt signaling

This article has been cited by other articles:

				B. C. Christensen, J. J. Godleski, C. J. Marsit, E. A. Houseman, C. Y. Lopez-Fagundo, J. L. Longacker, R. Bueno, D. J. Sugarbaker, H. H. Nelson, and K. T. Kelsey Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma Carcinogenesis, August 1, 2008; 29(8): 1555 - 1559. [Abstract] [Full Text] [PDF]

				H. Sato, H. Suzuki, M. Toyota, M. Nojima, R. Maruyama, S. Sasaki, H. Takagi, Y. Sogabe, Y. Sasaki, M. Idogawa, et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors Carcinogenesis, December 1, 2007; 28(12): 2459 - 2466. [Abstract] [Full Text] [PDF]

				N. Fujii, L. You, Z. Xu, K. Uematsu, J. Shan, B. He, I. Mikami, L. R. Edmondson, G. Neale, J. Zheng, et al. An Antagonist of Dishevelled Protein-Protein Interaction Suppresses {beta}-Catenin-Dependent Tumor Cell Growth Cancer Res., January 15, 2007; 67(2): 573 - 579. [Abstract] [Full Text] [PDF]

				L. Ai, Q. Tao, S. Zhong, C.R. Fields, W.-J. Kim, M. W. Lee, Y. Cui, K. D. Brown, and K. D. Robertson Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer Carcinogenesis, July 1, 2006; 27(7): 1341 - 1348. [Abstract] [Full Text] [PDF]

				S. Urakami, H. Shiina, H. Enokida, T. Kawakami, T. Tokizane, T. Ogishima, Y. Tanaka, L.-C. Li, L. A. Ribeiro-Filho, M. Terashima, et al. Epigenetic Inactivation of Wnt Inhibitory Factor-1 Plays an Important Role in Bladder Cancer through Aberrant Canonical Wnt/{beta}-Catenin Signaling Pathway Clin. Cancer Res., January 15, 2006; 12(2): 383 - 391. [Abstract] [Full Text] [PDF]

				C.-l. Huang, D. Liu, J. Nakano, S. Ishikawa, K. Kontani, H. Yokomise, and M. Ueno Wnt5a Expression Is Associated With the Tumor Proliferation and the Stromal Vascular Endothelial Growth Factor--An Expression in Non-Small-Cell Lung Cancer J. Clin. Oncol., December 1, 2005; 23(34): 8765 - 8773. [Abstract] [Full Text] [PDF]