Genetic and cellular studies highlight that A Disintegrin and Metalloproteinase 19 is a protective biomarker in human prostate cancer

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Abstract

Background

Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Current treatments include surgery, androgen ablation and radiation. Introduction of more targeted therapies in prostate cancer, based on a detailed knowledge of the signalling pathways, aims to reduce side effects, leading to better clinical outcomes for the patient. ADAM19 (A Disintegrin And Metalloproteinase 19) is a transmembrane and soluble protein which can regulate cell phenotype through cell adhesion and proteolysis. ADAM19 has been positively associated with numerous diseases, but has not been shown to be a tumor suppressor in the pathogenesis of any human cancers. Our group sought to investigate the role of ADAM19 in human prostate cancer.

Methods

ADAM19 mRNA and protein levels were assessed in well characterised human prostate cancer cohorts. ADAM19 expression was assessed in normal prostate epithelial cells (RWPE-1) and prostate cancer cells (LNCaP, PC3) using western blotting and immunocytochemistry. Proliferation assays were conducted in LNCaP cells in which ADAM19 was over-expressed. In vitro scratch assays were performed in PC3 cells over-expressing ADAM19.

Results

Immunohistochemical studies highlighted that ADAM19 protein levels were elevated in normal prostate tissue compared to prostate cancer biopsies. Results from the clinical cohorts demonstrated that high levels of ADAM19 in microarrays are positively associated with lower stage ( p = 0.02591) and reduced relapse ( p = 0.00277) of human prostate cancer. In vitro, ADAM19 expression was higher in RWPE-1 cells compared to LNCaP cells. In addition, human ADAM19 over-expression reduced LNCaP cell proliferation and PC3 cell migration.

Conclusions

Taken together, our immunohistochemical and microarray results and cellular studies have shown for the first time that ADAM19 is a protective factor for human prostate cancer. Further, this study suggests that upregulation of ADAM19 expression could be of therapeutic potential in human prostate cancer.

Electronic supplementary material

The online version of this article (doi:10.1186/s12885-016-2178-4) contains supplementary material, which is available to authorized users.

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Most cited references 44

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ADAM metalloproteinase disintegrins have emerged as the major proteinase family that mediates ectodomain shedding, the proteolytic release of extracellular domains from their membrane-bound precursors. Recent gene-manipulation studies have established the role of ADAM-mediated shedding in mammalian physiology and, in addition, raised the issue of functional redundancy among ADAM sheddases. ADAM sheddases activate, for example, growth factors and cytokines, thus regulating signalling pathways that are important in development and pathological processes such as cancer. The recent studies have also begun to elucidate the substrate specificity and the mechanisms that control ADAM-mediated shedding events that regulate, for example, growth-factor and Notch signalling, and the processing of the amyloid precursor protein.

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Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure.

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Recent studies have shown that lymphangiogenesis or the growth of lymphatic vessels at the periphery of tumors promotes tumor metastasis to lymph nodes. We show here that the fibronectin-binding integrin alpha4beta1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium. Tumors and lymphangiogenic growth factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGF-A, induce lymphatic vessel expression of integrin alpha4beta1. Integrin alpha4beta1 then promotes growth factor and tumor-induced lymphangiogenesis, as genetic loss of integrin alpha4beta1 expression in Tie2Cre+ alpha4(loxp/loxp) mice or genetic loss of alpha4 signaling in alpha4Y991A knock-in mice blocks growth factor and tumor-induced lymphangiogenesis, as well as tumor metastasis to lymph nodes. In addition, antagonists of integrin alpha4beta1 suppress lymphangiogenesis and tumor metastasis. Our studies show that integrin alpha4beta1 and the signals it transduces regulate the adhesion, migration, invasion, and survival of proliferating lymphatic endothelial cells. As suppression of alpha4beta1 expression, signal transduction, or function in tumor lymphatic endothelium not only inhibits tumor lymphangiogenesis but also prevents metastatic disease, these results show that integrin alpha4beta1-mediated tumor lymphangiogenesis promotes metastasis and is a useful target for the suppression of metastatic disease. (c) 2010 AACR.

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Author and article information

Contributors

Gerard Hoyne: gerard.hoyne@nd.edu.au

Caroline Rudnicka: caroline.rudnicka@uwa.edu.au

Qing-Xiang Sang: qxsang@chem.fsu.edu

Mark Roycik: dru.roycik@gmail.com

Sarah Howarth: sarahhowarth90@gmail.com

Peter Leedman: peter.leedman@perkins.uwa.edu.au

Markus Schlaich: markus.schlaich@uwa.edu.au

Patrick Candy: patrick.candy@perkins.uwa.edu.au

Vance Matthews: (61) 8 9224 0239 , vance.matthews@uwa.edu.au

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 24 February 2016

Publication date PMC-release: 24 February 2016

Publication date Collection: 2016

Volume: 16

Electronic Location Identifier: 151

Affiliations

[ ]School of Health Sciences and Institute of Health Science Research, The University of Notre Dame Australia, Fremantle Campus, Australia

[ ]Royal Perth Hospital, Perth, Australia

[ ]Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida USA

[ ]Harry Perkins Institute of Medical Research and the Centre for Medical Research, The University of Western Australia, Perth, Australia

[ ]School of Medicine and Pharmacology - Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia

[ ]School of Medicine and Pharmacology- Royal Perth Hospital Unit, Level 3, Medical Research Foundation Building, Rear 50 Murray Street, Perth, WA 6000 Australia

Article

Publisher ID: 2178

DOI: 10.1186/s12885-016-2178-4

PMC ID: 4766641

PubMed ID: 26912236

SO-VID: b31fe949-480f-4247-b093-07bc4daaa246

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 September 2015

Date accepted : 15 February 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001170, Cancer Council Western Australia;

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: adam19,prostate cancer,proliferation,metalloproteinase,microarray

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: adam19, prostate cancer, proliferation, metalloproteinase, microarray

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Genetic and cellular studies highlight that A Disintegrin and Metalloproteinase 19 is a protective biomarker in human prostate cancer

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 44

Shedding light on ADAM metalloproteinases.

Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure.

Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis.

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