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Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma

Authors' Affiliations: Departments of ¹ Cancer Biology, ² Pathology, and ³ Urology, Mayo Clinic Jacksonville, Jacksonville, Florida; ⁴ Department of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, Minnesota; ⁵ Bioinformatics Program, University of Texas Medical Branch, Galveston, Texas; ⁶ Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas; and ⁷ Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: John A. Copland, Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224. Phone: 904-953-6120; Fax: 904-953-0277; E-mail: copland.john{at}mayo.edu.

Purpose: Incidence and mortality rates for renal cell carcinoma (RCC) have been rising for decades. Unfortunately, the molecular events that support RCC carcinogenesis remain poorly understood. In an effort to gain a better understanding of signaling events in clear cell RCC (cRCC), we investigated the antitumor activity of secreted frizzled-related protein 1 (sFRP1), a negative regulator of Wnt signaling.

Experimental Design: Genomic profiling of cRCC tumors and patient-matched normal tissues was done and confirmed using quantitative PCR and immunohistochemistry. Methylation-specific PCR was done on patient samples to evaluate the mechanism responsible for sFRP1 loss. sFRP1 expression was restored in cRCC cells and the effects on tumor phenotype were characterized.

Results: Genomic profiling, quantitative PCR, and immunohistochemistry indicated that loss of sFRP1 occurred in cRCC and papillary RCC patient tissues. Twelve Wnt-regulated genes were up-regulated in cRCC tissues, including c-myc and cyclin D1, potentiators of cell proliferation and survival. Methylation of the sFRP1 gene was one mechanism identified for attenuation of sFRP1 mRNA. Stable reexpression of sFRP1 in cRCC cells resulted in decreased expression of Wnt target genes, decreased growth in cell culture, inhibition of anchorage-independent growth, and decreased tumor growth in athymic nude mice.

Conclusions: To our knowledge, this is the first report to show that stable restoration of sFRP1 expression in cRCC cells attenuates the cRCC tumor phenotype. Our data support a role for sFRP1 as a tumor suppressor in cRCC and that perhaps loss of sFRP1 is an early, aberrant molecular event in renal cell carcinogenesis.

Commentary

Loss of Secreted Frizzled-Related Protein-1 Expression in Renal Cell Carcinoma Reveals a Critical Tumor Suppressor Function

Jeffrey S. Rubin and Donald P. Bottaro
Clin. Cancer Res. 2007 13: 4660-4663. [Full Text] [PDF]

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