Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

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

Authors: Gerard Hoyne, Caroline Rudnicka, Qing-Xiang Sang, Mark Roycik, Sarah Howarth, Peter Leedman, Markus Schlaich, Patrick Candy, Vance Matthews

Published in: BMC Cancer | Issue 1/2016

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. IJC. 2015;136(5):E359–86.
2.
Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1(1):34–45.CrossRefPubMed
3.
Gingrich JR, Barrios RJ, Kattan MW, Nahm HS, Finegold MJ, Greenberg NM. Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res. 1997;57(21):4687–91.PubMed
4.
Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology. 2003;61(2):32–8.CrossRefPubMed
5.
Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98–107.CrossRefPubMed
6.
Giovannucci E. Insulin-like growth factor-I and binding protein-3 and risk of cancer. Horm Res. 1999;51(3):34–41.CrossRefPubMed
7.
Grzmil M, Hemmerlein B, Thelen P, Schweyer S, Burfeind P. Blockade of the type I IGF receptor expression in human prostate cancer cells inhibits proliferation and invasion, up-regulates IGF binding protein-3, and suppresses MMP-2 expression. J Pathol. 2004;202(1):50–9.CrossRefPubMed
8.
Huovila APJ, Turner AJ, Pelto-Huikko M, Kärkkäinen I, Ortiz RM. Shedding light on ADAM metalloproteinases. Trends Biochem Sci. 2005;30(7):413–22.CrossRefPubMed
9.
Fritzsche FR, Jung M, Tölle A, Wild P, Hartmann A, Wassermann K, et al. ADAM9 expression is a significant and independent prognostic marker of PSA relapse in prostate cancer. Eur Urol. 2008;54(5):1097–108.CrossRefPubMed
10.
Josson S, Anderson CS, Sung SY, Johnstone PA, Kubo H, Hsieh CL, et al. Inhibition of ADAM9 expression induces epithelial phenotypic alterations and sensitizes human prostate cancer cells to radiation and chemotherapy. Prostate. 2011;71(3):232–40.PubMedCentralCrossRefPubMed
11.
Arima T, Enokida H, Kubo H, Kagara I, Matsuda R, Toki K, et al. Nuclear translocation of ADAM10 contributes to the pathogenesis and progression of human prostate cancer. Cancer Sci. 2007;98(11):1720–6.CrossRefPubMed
12.
Kuefer R, Day KC, Kleer CG, Sabel MS, Hofer MD, Varambally S, et al. ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease. Neoplasia. 2006;8(4):319–29.PubMedCentralCrossRefPubMed
13.
Xiao LJ, Lin P, Lin F, Liu X, Qin W, Zou HF, et al. ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion. Int J Oncol. 2012;40(5):1714–24.PubMed
14.
Qi B, Newcomer RG, Sang QXA. ADAM19/adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases. Curr Pharm Des. 2009;15(20):2336–48.CrossRefPubMed
15.
Wei P, Zhao Y-G, Zhuang L, Ruben S, Sang Q-XA. Expression and enzymatic activity of human disintegrin and metalloproteinase ADAM19/meltrin beta. Biochem Biophys Res Commun. 2001;280:744–55.CrossRefPubMed
16.
Inoue D, Reid M, Lum L, Kratzschmar J, Weskamp G, Myung YM, et al. Cloning and Initial characterization of mouse meltrin b and analysis of the expression of four metalloprotease-disintegrins in bone cells. J Biol Chem. 1998;273(7):4180–7.CrossRefPubMed
17.
Kurisakia T, Masudaa A, Osumib N, Nabeshimaa Y-i, Fujisawa-Seharaa A. Spatially- and temporally-restricted expression of meltrin a (ADAM12) and b (ADAM19) in mouse embryo. Mech Dev. 1998;73(2):211–5.CrossRef
18.
Zhou HM, Weskamp G, Chesneau V, Sahin U, Vortkamp A, Horiuchi K, et al. Essential role for ADAM19 in cardiovascular morphogenesis. Mol Cell Biol. 2004;24(1):96–104.PubMedCentralCrossRefPubMed
19.
LeBrasseur NK, Mizer KC, Parkington JD, Sawyer DB, Fielding RA. The expression of neuregulin and erbB receptors in human skeletal muscle: effects of progressive resistance training. Eur J Appl Physiol. 2005;94(4):371–5.CrossRefPubMed
20.
Huang J, Bridges LC, White JM. Selective modulation of integrin-mediated cell migration by distinct ADAM family members. Mol Biol Cell. 2005;16(10):4982–91.PubMedCentralCrossRefPubMed
21.
Garmy-Susini B, Avraamides CJ, Schmid MC, Foubert P, Ellies LG, Barnes L, et al. Integrin α4β1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res. 2010;70(8):3042–51.PubMedCentralCrossRefPubMed
22.
Zhao Y-G, Wei P, Sang Q-XA. Inhibitory antibodies against endopeptidase activity of human adamalysin 19. Biochem Biophys Res Commun. 2001;289:288–94.CrossRefPubMed
23.
Kang T, Park H, Suh Y, Zhao Y, Tschesche H, Sang Q. Autolytic processing at Glu586-Ser587 within the cysteine-rich domain of human adamalysin 19/disintegrin-metalloproteinase 19 is necessary for its proteolytic activity. J Biol Chem. 2002;277(50):48514–22.CrossRefPubMed
24.
Althoff K, Reddy P, Voltz N, Rose-John S, Müllberg J. Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of transmembrane proteins. Eur J Biochem. 2000;267(9):2624–31.CrossRefPubMed
25.
Liang C, Park AY, Guan J. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2(2):329–33.CrossRefPubMed
26.
Hikita A, Tanaka N, Yamane S, Ikeda Y, Furukawa H, Tohma S, et al. Involvement of A Disintegrin and Metalloproteinase 10 and 17 in shedding of tumor necrosis factor-α. Biochem Cell Biol. 2009;87(4):581–93.CrossRefPubMed
27.
Franzè E, Caruso R, Stolfi C, Sarra M, Cupi M, Ascolani M, et al. High expression of the “A Disintegrin And Metalloprotease” 19 (ADAM19), a sheddase for TNF-α in the mucosa of patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2013;19(3):501–11.CrossRefPubMed
28.
Chan M, Huang Y, Hartman-Frey C, Kuo C, Deatherage D, Qin H, et al. Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer. Neoplasia. 2008;10(9):908.PubMedCentralCrossRefPubMed
29.
Melenhorst W, Heuvel M, Timmer A, Huitema S, Bulthuis M, Timens W, et al. ADAM19 expression in human nephrogenesis and renal disease: associations with clinical and structural deterioration. Kidney Int. 2006;70(7):1269–78.CrossRefPubMed
30.
Wildeboer D, Naus S, Sang Q, Bartsch J, Pagenstecher A. Metalloproteinase disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness. J Neuropathol Exp Neurol. 2006;65(5):516–27.CrossRefPubMed
31.
Shirakabe K, Wakatsuki S, Kurisaki T, Fujisawa-Sehara A. Roles of Meltrin β/ADAM19 in the processing of neuregulin. J Biol Chem. 2001;276(12):9352–8.CrossRefPubMed
32.
Chesneau V, Becherer J, Zheng Y, Erdjument-Bromage H, Tempst P, Blobel C. Catalytic properties of ADAM19. J Biol Chem. 2003;278(25):22331–40.CrossRefPubMed
33.
Tanabe C, Hotoda N, Sasagawa N, Futai E, Komano H, Ishiura S. ADAM19 autolysis is activated by LPS and promotes non-classical secretion of cysteine-rich protein 2. Biochem Biophys Res Commun. 2010;396(4):927–32.CrossRefPubMed
34.
Kurohara K, Komatsu K, Kurisaki T, Masuda A, Irie N, Asano M, et al. Essential roles of Meltrin β (ADAM19) in heart development. Dev Biol. 2004;267(1):14–28.CrossRefPubMed
35.
Chen C, Huang X, Sheppard D. ADAM33 is not essential for growth and development and does not modulate allergic asthma in mice. Mol Cell Biol. 2006;26(18):6950–6.PubMedCentralCrossRefPubMed
36.
Lemmens K, Doggen K, Keulenaer GD. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease implications for therapy of heart failure. Circulation. 2007;116(8):954–60.CrossRefPubMed
37.
Grasso A, Wen D, Miller C, Rhim J, Pretlow T, Kung H. ErbB kinases and NDF signaling in human prostate cancer cells. Oncogene. 1997;15(22):2705–16.CrossRefPubMed
38.
Wakatsuki S, Kurisaki T, Sehara-Fujisawa A. Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin β/ADAM19. J Neurochem. 2004;89(1):119–23.CrossRefPubMed
39.
Chopra D, Menard R, Januszewski J, Mattingly R. TNF-α-mediated apoptosis in normal human prostate epithelial cells and tumor cell lines. Cancer Lett. 2004;203(2):145–54.CrossRefPubMed
40.
Rokhlin O, Taghiyev A, Guseva N, Glover R, Chumakov P, Kravchenko J, et al. Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP. Oncogene. 2005;24(45):6773–84.PubMedCentralCrossRefPubMed
41.
Cheung A, Ko J, Lung H, Chan K, Stanbridge E, Zabarovsky E, et al. Cysteine-rich intestinal protein 2 (CRIP2) acts as a repressor of NF-κB–mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis. Proc Natl Acad Sci U S A. 2011;108(20):8390–5.PubMedCentralCrossRefPubMed
42.
Lo P, Ko J, Yu Z, Law S, Wang L, Li J, et al. The LIM domain protein, CRIP2, promotes apoptosis in esophageal squamous cell carcinoma. Cancer Lett. 2012;316(1):39–45.CrossRefPubMed
43.
Gallagher MF, Salley Y, Spillane CD, Ffrench B, Baruni SE, Blacksheilds G, et al. Enhanced regulation of cell cycle and suppression of osteoblast differentiation molecular signatures by prostate cancer stem-like holoclones. J Clin Path. 2015;68:692–702.CrossRefPubMed
44.
MA MK, Ohta K, Egashira M, Jinno Y, Niikawa N, Matsuda I, et al. Human ESP1/CRP2, a member of the LIM domain protein family: characterization of the cDNA and assignment of the gene locus to chromosome 14q32.3. Genomics. 1996;31(2):167–76.CrossRef
45.
Shen X, Falzon M. PTH-related protein modulates PC-3 prostate cancer cell adhesion and integrin subunit profile. Mol Cell Endo. 2003;199(1):165–77.CrossRef
46.
Angulo JC, Adres G, Ashour N, Sanchez-Chapado M, Lopez JI, Ropero S. Development of castration resistant prostate cancer can be predicted by a DNA hypermethylation profile. J Urol. 2016;195:1–8.CrossRef
47.
London S, Gao W, Gharib S, Hancock D, Wilk J, House J, et al. ADAM19 and HTR4 variants and pulmonary function: cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium targeted sequencing study. Circ Cardiovasc Genet. 2014;7(3):350–8.PubMedCentralCrossRefPubMed
Metadata
Title
Genetic and cellular studies highlight that A Disintegrin and Metalloproteinase 19 is a protective biomarker in human prostate cancer
Authors
Gerard Hoyne
Caroline Rudnicka
Qing-Xiang Sang
Mark Roycik
Sarah Howarth
Peter Leedman
Markus Schlaich
Patrick Candy
Vance Matthews
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2178-4

Other articles of this Issue 1/2016

BMC Cancer 1/2016 Go to the issue

Research article

Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

Research article

Urgent surgery after emergency presentation for colorectal cancer has no impact on overall and disease-free survival: a propensity score analysis

Research article

Tumor-suppressive effects of atelocollagen-conjugated hsa-miR-520d-5p on un-differentiated cancer cells in a mouse xenograft model

Research article

Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma

Research article

High level of serum apolipoprotein A-I is a favorable prognostic factor for overall survival in esophageal squamous cell carcinoma

Study protocol

A comparative study on the efficacies of gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist in neoadjuvant androgen deprivation therapy combined with transperineal prostate brachytherapy for localized prostate cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits