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Author Notes:

E-mail: leland.chung@cshs.org (LWKC); haiyen.zhau@cshs.org (HEZ).

Conceived and designed the experiments: HWL HEZ LWKC.

Performed the experiments: XJY RXW WPQ.

Analyzed the data: RZHX RL AOO BPZ MZ.

Contributed reagents/materials/analysis tools: RLV ZRL.

Wrote the paper: HWL RXW HEZ LWKC.

The authors have declared that no competing interests exist.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Research Funding:

This work is supported by research grants 2PO1CA098912 and 5RO1CA122602 (LWKC) of the National Institutes of Health/National Cancer Institute (http://www.nih.gov) and W81XWH-07-0172 (LWKC) of the Department of Defense of the United States (http://cdmrp.army.mil/pcrp).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • ESTROGEN-REGULATED GENES
  • TRANSCRIPTION FACTOR SNAIL
  • E-CADHERIN EXPRESSION
  • BREAST-CANCER
  • GROWTH-FACTOR
  • TUMOR PROGRESSION
  • ZINC TRANSPORTERS
  • CELLS
  • RECEPTOR
  • MCF-7
  • Urology

LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK Signaling

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Journal Title:

PLoS ONE

Volume:

Volume 6, Number 11

Publisher:

, Pages e27720-e27720

Type of Work:

Article | Final Publisher PDF

Abstract:

LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition (EMT) in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there was no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In the present communication, we found increased LIV-1 expression in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives human prostate cancer EMT in an androgen-refractory prostate cancer cells (ARCaP) prostate cancer bone metastasis model. LIV-1, when overexpressed in ARCaP E (derivative cells of ARCaP with epithelial phenotype) cells, promoted EMT irreversibly. LIV-1 overexpressed ARCaP E cells had elevated levels of HB-EGF and matrix metalloproteinase (MMP) 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor (HB-EGF) from ARCaP E cells that elicited constitutive epidermal growth factor receptor (EGFR) phosphorylation and its downstream extracellular signal regulated kinase (ERK) signaling. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promoted EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases.

Copyright information:

© 2011 Lue et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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