Androgens induce functional CXCR4 through ERG factor expression in TMPRSS2-ERG fusion-positive prostate cancer cells. Transl Oncol 3:195-203

Department of Urology, Wayne State University School of Medicine, Detroit, MI, USA.
Translational oncology (Impact Factor: 2.88). 06/2010; 3(3):195-203. DOI: 10.1593/tlo.09328
Source: PubMed


TMPRSS2-ERG fusion transcripts have been shown to be expressed in a majority of prostate cancer (PC) patients because of chromosomal translocations or deletions involving the TMPRSS2 gene promoter and the ERG gene coding sequence. These alterations cause androgen-dependent ERG transcription factor expression in PC patients. We and others have shown that chemokine receptor CXCR4 expression is upregulated in PC tumor cells, and its ligand, CXCL12, is expressed in bone stromal cells. The CXCL12/CXCR4 axis functions in PC progression to enhance invasion and metastasis. To address the regulation of CXCR4 expression, we identified several putative ERG consensus-binding sites in the promoter region of CXCR4. We hypothesized that androgen-dependent regulation of the ERG transcription factor could induce CXCR4 expression in PC cells. Results of the current study show that 1) prostate tumor cells coexpress higher ERG and CXCR4 compared with benign tissue, 2) CXCR4 expression is increased in the TMPRSS2-ERG fusion-positive cell line, 3) ERG transcription factor binds to the CXCR4 gene promoter, 4) synthetic androgen (R1881) upregulates both ERG and CXCR4 in TMPRSS2-ERG fusion-positive VCaP cells, 5) small interfering RNA-mediated down-regulation of ERG resulted in the loss of androgen-dependent regulation of CXCR4 expression in VCaP cells, and 6) R1881-activated TMPRSS2-ERG expression functionally activates CXCR4 in VCaP cells. These findings provide a link between TMPRSS2-ERG translocations and enhanced metastasis of tumor cells through CXCR4 function in PC cells.

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Available from: Pridvi Kandagatla, Jun 25, 2015
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    • "In the CXCR4 promoter, several consensus sequences of ERG binding sites were identified and it was noted that an androgen agonist (R1881) can induce the mRNA expressions of both ERG and CXCR4 genes in TMPRSS2-ERG fusion-positive VCaP cells. Conversely, targeted inhibition of ERG by siRNA can inhibit the gene expressions of ERG and CXCR4 and prevents the upregulation of the androgen-induced CXCR4 expression in VCaP cells [83]. However, it is also relevant to mention that CXCR4 is negatively regulated by miR-139. "
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    ABSTRACT: Prostate cancer is a gland tumor in the male reproductive system. It is a multifaceted and genomically complex disease. Transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 homolog (TMPRSS2-ERG) gene fusions are the common molecular signature of prostate cancer. Although tremendous advances have been made in unraveling various facets of TMPRSS2-ERG-positive prostate cancer, many research findings must be sequentially collected and re-interpreted. It is important to understand the activation or repression of target genes and proteins in response to various stimuli and the assembly in signal transduction in TMPRSS2-ERG fusion-positive prostate cancer cells. Accordingly, we divide this multi-component review ofprostate cancer cells into several segments: 1) The role of TMPRSS2-ERG fusion in genomic instability and methylated regulation in prostate cancer and normal cells; 2) Signal transduction cascades in TMPRSS2-ERG fusion-positive prostate cancer; 3) Overexpressed genes in TMPRSS2-ERG fusion-positive prostate cancer cells; 4) miRNA mediated regulation of the androgen receptor (AR) and its associated protein network; 5) Quantitative control of ERG in prostate cancer cells; 6) TMPRSS2-ERG encoded protein targeting; In conclusion, we provide a detailed understanding of TMPRSS2-ERG fusion related information in prostate cancer development to provide a rationale for exploring TMPRSS2-ERG fusion-mediated molecular network machinery.
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    • "In the majority of cancers, cell invasion and migration are the key features of aggressive nature of tumors towards metastasis. ERG regulates invasion and migration related genes in CaP such as MMP1, MMP3, MMP9, and ADAM19, the urokinase plasminogen activator (PLAU), and the plasminogen activator inhibitor type1 in CaP.[99–101] ERG enhances cell invasion and metastasis through regulating CXCR4, a chemokine receptor.[27102] ERG also induces the expression of osteopontin (OPN) through ETS binding sequences within the promoter.[103] "
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    ABSTRACT: Prevalent gene fusions involving regulatory sequences of the androgen receptor (AR) regulated genes (primarily TMPRSS2) and protein coding sequences of nuclear transcription factors of the ETS gene family (predominantly ERG) result in unscheduled androgen dependent ERG expression in prostate cancer (CaP).Cumulative data from a large number of studies in the past six years accentuate ERG alterations in more than half of all CaP patients in Western countries. Studies underscore that ERG functions are involved in the biology of CaP. ERG expression in normal context is selective to endothelial cells, specific hematopoetic cells and pre-cartilage cells. Normal functions of ERG are highlighted in hematopoetic stem cells. Emerging data continues to unravel molecular and cellular mechanisms by which ERG may contribute to CaP. Herein, we focus on biological and clinical aspects of ERG oncogenic alterations, potential of ERG-based stratification of CaP and the possibilities of targeting the ERG network in developing new therapeutic strategies for the disease.
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