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Mechanisms and functional consequences of PDEF protein expression loss during prostate cancer progression

Authors

  • David P. Turner,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
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    • Both the authors contributed equally.

  • Victoria J. Findlay,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
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    • Both the authors contributed equally.

  • Omar Moussa,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
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  • Victor I. Semenchenko,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
    Current affiliation:
    1. NuGEN, San Carlos, CA.
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  • Patricia M. Watson,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
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  • Amanda C. LaRue,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
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  • Mohamed M. Desouki,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
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  • Mostafa Fraig,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
    Current affiliation:
    1. Department of Pathology, University of Louisville, Louisville, KY.
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  • Dennis K. Watson

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
    2. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC
    3. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
    • Hollings Cancer Center, Room H0310, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425.
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Abstract

BACKGROUND

Ets is a large family of transcriptional regulators with functions in most biological processes. While the Ets family gene, prostate-derived epithelial factor (PDEF), is expressed in epithelial tissues, PDEF protein expression has been found to be reduced or lost during cancer progression. The goal of this study was to examine the mechanism for and biologic impact of altered PDEF expression in prostate cancer.

METHODS

PDEF protein expression of prostate specimens was examined by immunohistochemistry. RNA and protein expression in cell lines were measured by q-PCR and Western blot, respectively. Cellular growth was determined by quantifying viable and apoptotic cells over time. Cell cycle was measured by flow cytometry. Migration and invasion were determined by transwell assays. PDEF promoter occupancy was determined by chromatin immunoprecipitation (ChIP).

RESULTS

While normal prostate epithelium expresses PDEF mRNA and protein, tumors show no or decreased PDEF protein expression. Re-expression of PDEF in prostate cancer cells inhibits cell growth. PDEF expression is inversely correlated with survivin, urokinase plasminogen activator (uPA) and slug expression and ChIP studies identify survivin and uPA as direct transcriptional targets of PDEF. This study also shows that PDEF expression is regulated via a functional microRNA-204 (miR-204) binding site within the 3′UTR. Furthermore, we demonstrate the biologic significance of miR-204 expression and that miR-204 is over-expressed in human prostate cancer specimens.

CONCLUSIONS

Collectively, the reported studies demonstrate that PDEF is a negative regulator of tumor progression and that the miR-204-PDEF regulatory axis contributes to PDEF protein loss and resultant cancer progression. Prostate 71:1723–1735, 2011. © 2011 Wiley Periodicals, Inc.

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