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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Androgens Induce Functional CXCR4 through ERG Factor Expression in TMPRSS2-ERG Fusion-Positive Prostate Cancer Cells

Juan Cai1, Pridvi Kandagatla, Rajareddy Singareddy

  • 1Department of Urology, Wayne State University School of Medicine, Detroit, MI, USA.

Translational Oncology
|June 22, 2010
PubMed

Insights

Prostate cancer (PC) cells with TMPRSS2-ERG fusions show increased CXCR4. Androgen-driven ERG directly upregulates CXCR4, promoting PC metastasis via the CXCL12/CXCR4 axis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • TMPRSS2-ERG fusion transcripts are common in prostate cancer (PC), leading to androgen-dependent ERG expression.
  • CXCR4 is upregulated in PC cells, and its ligand CXCL12 is found in bone stromal cells, facilitating PC invasion and metastasis.

Purpose of the Study:

  • To investigate the hypothesis that androgen-dependent ERG transcription factor induces CXCR4 expression in PC cells.
  • To elucidate the regulatory mechanism of CXCR4 expression in PC.

Main Methods:

  • Analysis of ERG and CXCR4 coexpression in prostate tumor versus benign tissue.
  • Assessing CXCR4 expression in a TMPRSS2-ERG fusion-positive cell line.
  • Chromatin immunoprecipitation to determine ERG binding to the CXCR4 promoter.
  • Androgen stimulation (R1881) and small interfering RNA (siRNA) knockdown of ERG in VCaP cells to assess functional effects on CXCR4.

Main Results:

  • Prostate tumor cells exhibit higher ERG and CXCR4 coexpression than benign tissues.
  • TMPRSS2-ERG fusion-positive cell lines show increased CXCR4 expression.
  • ERG transcription factor directly binds to the CXCR4 gene promoter.
  • Androgen stimulation upregulates both ERG and CXCR4 in VCaP cells.
  • ERG knockdown abolishes androgen-dependent CXCR4 regulation in VCaP cells.
  • Activated TMPRSS2-ERG functionally upregulates CXCR4 in VCaP cells.

Conclusions:

  • Findings establish a direct link between TMPRSS2-ERG fusions and enhanced CXCR4 expression in PC.
  • Androgen-driven ERG upregulates CXCR4, contributing to PC cell invasion and metastasis.
  • The study identifies a key molecular pathway (ERG-CXCR4 axis) driving prostate cancer progression.

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