Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma

Michelle L. Gumz, Hongzhi Zou, Pamela A. Kreinest, April C. Childs, Leandra S. Belmonte, Shauna N. LeGrand, Kevin J. Wu, Bruce A. Luxon, Mala Sinha, Alexander S. Parker, L. Z. Sun, David A. Ahlquist, Christopher G. Wood, John A. Copland

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    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)4740-4749
    Number of pages10
    JournalClinical Cancer Research
    Volume13
    Issue number16
    DOIs
    StatePublished - Aug 15 2007

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    Renal Cell Carcinoma
    Phenotype
    Neoplasms
    Nude Mice
    Polymerase Chain Reaction
    Methylation
    frizzled related protein-1
    Carcinogenesis
    Growth
    Immunohistochemistry
    Genes
    Cyclin D1
    Cell Survival
    Research Design
    Cell Culture Techniques
    Cell Proliferation
    Kidney
    Messenger RNA

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Gumz, M. L., Zou, H., Kreinest, P. A., Childs, A. C., Belmonte, L. S., LeGrand, S. N., ... Copland, J. A. (2007). Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. Clinical Cancer Research, 13(16), 4740-4749. https://doi.org/10.1158/1078-0432.CCR-07-0143

    Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. / Gumz, Michelle L.; Zou, Hongzhi; Kreinest, Pamela A.; Childs, April C.; Belmonte, Leandra S.; LeGrand, Shauna N.; Wu, Kevin J.; Luxon, Bruce A.; Sinha, Mala; Parker, Alexander S.; Sun, L. Z.; Ahlquist, David A.; Wood, Christopher G.; Copland, John A.

    In: Clinical Cancer Research, Vol. 13, No. 16, 15.08.2007, p. 4740-4749.

    Research output: Contribution to journalArticle

    Gumz, ML, Zou, H, Kreinest, PA, Childs, AC, Belmonte, LS, LeGrand, SN, Wu, KJ, Luxon, BA, Sinha, M, Parker, AS, Sun, LZ, Ahlquist, DA, Wood, CG & Copland, JA 2007, 'Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma', Clinical Cancer Research, vol. 13, no. 16, pp. 4740-4749. https://doi.org/10.1158/1078-0432.CCR-07-0143
    Gumz, Michelle L. ; Zou, Hongzhi ; Kreinest, Pamela A. ; Childs, April C. ; Belmonte, Leandra S. ; LeGrand, Shauna N. ; Wu, Kevin J. ; Luxon, Bruce A. ; Sinha, Mala ; Parker, Alexander S. ; Sun, L. Z. ; Ahlquist, David A. ; Wood, Christopher G. ; Copland, John A. / Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 16. pp. 4740-4749.
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    abstract = "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.",
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    T1 - Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma

    AU - Gumz, Michelle L.

    AU - Zou, Hongzhi

    AU - Kreinest, Pamela A.

    AU - Childs, April C.

    AU - Belmonte, Leandra S.

    AU - LeGrand, Shauna N.

    AU - Wu, Kevin J.

    AU - Luxon, Bruce A.

    AU - Sinha, Mala

    AU - Parker, Alexander S.

    AU - Sun, L. Z.

    AU - Ahlquist, David A.

    AU - Wood, Christopher G.

    AU - Copland, John A.

    PY - 2007/8/15

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    N2 - 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.

    AB - 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.

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