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Tumor Biology

, Volume 36, Issue 5, pp 3565–3572 | Cite as

Overexpression of ETV4 is associated with poor prognosis in prostate cancer: involvement of uPA/uPAR and MMPs

  • Mei Qi
  • Zhiyan Liu
  • Chengwu Shen
  • Lin Wang
  • Jiping Zeng
  • Chunni Wang
  • Congcong Li
  • Weiwei Fu
  • Yi Sun
  • Bo Han
Research Article

Abstract

ETS gene fusions involving ERG, ETV1, ETV4, ETV5, and FLI1 define a distinct class of prostate cancer (PCa), and this might have a bearing on diagnosis, prognosis, and rational therapeutic targeting. In the current study, we focused on the clinicopathological significance of ETV4 in Chinese PCa patients and the mechanisms whereby ETV4 overexpression mediates tumor invasion in the prostate. Overall, ETV4 overexpression was identified in 30.4 % (45/148) of PCa cases by immunohistochemistry. Accordingly, ETV4 was rearranged in only 1.6 % (2/128) of PCa patients. Clinically, ETV4 overexpression was significantly correlated with Gleason score (P = 0.045) and pathological tumor stage (P = 0.041). Multivariate Cox regression analysis indicated that ETV4 is an unfavorable independent prognostic factor (P = 0.040). Functional studies further showed that small interfering RNA (siRNA) knockdown of ETV4 significantly decreases proliferation and invasion of PC-3 cell and partially reverses epithelial-mesenchymal transition in vitro. Notably, ETV4 knockdown significantly downregulated expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) at messenger RNA (mRNA) and protein levels. Chromatin immunoprecipitation assay demonstrated that ETV4 regulates uPA expression through direct binding to its promoter region. Additionally, ETV4 knockdown was also observed to significantly inhibit expression of matrix metalloproteinase (MMP)-2 and MMP-9. In conclusion, for the first time, our study suggested that ETV4 is an independent poor prognostic factor in Chinese PCa patients. Silencing of ETV4 suppresses invasion of PCa cells by inhibiting the expression of uPA/uPAR as well as MMPs. Further studies will be needed to determine whether ETV4 could be regarded as a potential target for the management and prevention of PCa.

Keywords

ETV4 Prostate cancer Prognosis uPA/uPAR MMP Invasion 

Notes

Acknowledgments

Supported by the National Natural Science Foundation of China (Grant No. 81171951); China Postdoctoral Science Foundation Funded Project (Project No. 2012 M521344); Natural Science Foundation of Shandong Province (Grant No. ZR2011HQ040),

Conflicts of interest

None

Supplementary material

13277_2014_2993_MOESM1_ESM.xls (26 kb)
ESM 1 (XLS 26 kb)
13277_2014_2993_MOESM2_ESM.xls (28 kb)
ESM 2 (XLS 27 kb)
13277_2014_2993_Fig5_ESM.gif (10 kb)
Supplementary Fig. 1

The alteration of uPA and uPAR mRNA level in PC-3 cells. The uPA and uPAR mRNA levels after exposure of 10ng/ml rUPA was quantified by qRT-PCR in PC-3 cells after ETV4 silencing (*p<0.05, compared to the control). Con, control group; rUPA, recombinant uPA protein (GIF 9 kb)

13277_2014_2993_MOESM3_ESM.tif (125 kb)
High resolution image (TIFF 125 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Mei Qi
    • 1
  • Zhiyan Liu
    • 1
  • Chengwu Shen
    • 2
  • Lin Wang
    • 1
    • 3
  • Jiping Zeng
    • 4
  • Chunni Wang
    • 1
  • Congcong Li
    • 1
  • Weiwei Fu
    • 5
  • Yi Sun
    • 1
  • Bo Han
    • 1
    • 6
  1. 1.Department of PathologyShandong University Medical SchoolJinanChina
  2. 2.Department of PharmacyShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  3. 3.Research Center for Medicinal Biotechnology, Key Laboratory for Rare & Uncommon Diseases of Shandong ProvinceShandong Academy of Medical SciencesJinanChina
  4. 4.Department of BiochemistryShandong University, School of MedicineJinanChina
  5. 5.Department of PathologyThe Affiliated Hospital of Qingdao University Medical CollegeQingdaoChina
  6. 6.Department of PathologyQilu Hospital of Shandong UniversityJinanChina

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