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Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells

  1. Ben-Yi Li1,2,3,4,*,
  2. Xin-Bo Liao1,
  3. Atsuya Fujito1,
  4. J. Brantley Thrasher1,4,
  5. Fang-Yun Shen5,
  6. Ping-Yi Xu6,*

Article first published online: 8 JAN 2007

DOI: 10.1111/j.1745-7262.2007.00226.x

Issue

Asian Journal of Andrology

Asian Journal of Andrology

Volume 9, Issue 1, pages 41–50, January 2007

Additional Information

How to Cite

Li, B.-Y., Liao, X.-B., Fujito, A., Thrasher, J. B., Shen, F.-Y. and Xu, P.-Y. (2007), Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells. Asian Journal of Andrology, 9: 41–50. doi: 10.1111/j.1745-7262.2007.00226.x

Author Information

  1. 1

    Department of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USA

  2. 2

    Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA

  3. 3

    Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160

  4. 4

    Department of Kansas Masonic Cancer Research Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA

  5. 5

    Department of Urology, The Affiliated Shenzhen Sun Hospital, Dalian Medical University, Shenzhen 518001, China

  6. 6

    Department of Neurology, Sun Yat-Sen University, Guangzhou 510080, China

* Ben-Yi Li, MD, PhD, Department of Urology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. Tel: +1-913-588-4773 Fax: +1-913-588-4756 E-mail: bli@kumc.edu
Dr Ping-Yi Xu, Department of Neurology, Sun Yat-Sen University, Guangzhou 510080, China. Tel: +86-20-8733-4438 Email: pxu@kumc.edu

Publication History

  1. Issue published online: 8 JAN 2007
  2. Article first published online: 8 JAN 2007
  3. Received 2006-05-12 Accepted 2006-07-12

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Keywords:

  • androgen;
  • androgen receptor;
  • androgen response element;
  • matrix metalloproteinases-2;
  • promoter;
  • prostate cancer

Abstract

Aim: To characterize the matrix metalloproteinases (MMP)-2 promoter and to identify androgen response elements (AREs) involved in androgen-induced MMP-2 expression. Methods: MMP-2 mRNA levels was determined by reverse transcription-polymerase chain reaction (RT-PCR). MMP-2 promoter-driven luciferase assays were used to determine the fragments responsible for androgen-induced activity. Chromatin-immunoprecipitation assay and electrophoretic mobility shift assays (EMSA) were used to verify the identified AREs in the MMP-2 promoter. Results: Androgen significantly induced MMP-2 expression at the mRNA level, which was blocked by the androgen antagonist bicalutamide. Deletion of a region encompassing base pairs -1591 to -1259 (relative to the start codon) of the MMP-2 promoter led to a significant loss of androgen-induced reporter activity. Additional deletion of the 5′-region up to -562 bp further reduced the androgen-induced MMP-2 promoter activity. Sequence analysis of these two regions revealed two putative ARE motifs. Introducing mutations in the putative ARE motifs by site-directed mutagenesis approach resulted in a dramatic loss of androgen-induced MMP-2 promoter activity, indicating that the putative ARE motifs are required for androgen-stimulated MMP-2 expression. Most importantly, the androgen receptor (AR) interacted with both motif-containing promoter regions in vivo in a chromatin immunoprecipitation assay after androgen treatment. Furthermore, the AR specifically bound to the wild-type but not mutated ARE motifs-containing probes in an in vitro EMSA assay. Conclusion: Two ARE motifs were identified to be responsible for androgen-induced MMP-2 expression in prostate cancer cells.

Edited by Prof. Chawnshang Chang

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