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Prostate Cancer

Low-Molecular-Weight Protein Tyrosine Phosphatase Predicts Prostate Cancer Outcome by Increasing the Metastatic Potential

By: Roberta R. Ruela-de-Sousaa b , Elmer Hoekstraa , A. Marije Hooglandc, Karla C. Souza Queirozb d, Maikel P. Peppelenboscha, Andrew P. Stubbse, Karin Pelizzaro-Rochab, Geert J.L.H. van Leendersc, Guido Jensterf, Hiroshi Aoyamab, Carmen V. Ferreirab and Gwenny M. Fuhlera

European Urology, Volume 69 Issue 4, April 2016, Pages 710-719

Published online: 01 April 2016

Keywords: Biomarker, Metastasis, Phosphatases, Prostate cancer

Abstract Full Text Full Text PDF (4,4 MB) Patient Summary

Abstract

Background

Low-risk patients suffering from prostate cancer (PCa) are currently placed under active surveillance rather than undergoing radical prostatectomy. However, clear parameters for selecting the right patient for each strategy are not available, and new biomarkers and treatment modalities are needed. Low-molecular-weight protein tyrosine phosphatase (LMWPTP) could present such a target.

Objective

To correlate expression levels of LMWPTP in primary PCa to clinical outcome, and determine the role of LMWPTP in prostate tumor cell biology.

Design, setting, and participants

Acid phosphatase 1, soluble (ACP1) expression was analyzed on microarray data sets, which were subsequently used in Ingenuity Pathway Analysis. Immunohistochemistry was performed on a tissue microarray containing material of 481 PCa patients whose clinicopathologic data were recorded. PCa cell line models were used to investigate the role of LMWPTP in cell proliferation, migration, adhesion, and anoikis resistance.

Outcome measurements and statistical analysis

The association between LMWPTP expression and clinical and pathologic outcomes was calculated using chi-square correlations and multivariable Cox regression analysis. Functional consequences of LMWPTP overexpression or downregulation were determined using migration and adhesion assays, confocal microscopy, Western blotting, and proliferation assays.

Results and limitations

LMWPTP expression was significantly increased in human PCa and correlated with earlier recurrence of disease (hazard ratio [HR]:1.99; p < 0.001) and reduced patient survival (HR: 1.53; p = 0.04). Unbiased Ingenuity analysis comparing cancer and normal prostate suggests migratory propensities in PCa. Indeed, overexpression of LMWPTP increases PCa cell migration, anoikis resistance, and reduces activation of focal adhesion kinase/paxillin, corresponding to decreased adherence.

Conclusions

Overexpression of LMWPTP in PCa confers a malignant phenotype with worse clinical outcome. Prospective follow-up should determine the clinical potential of LMWPTP overexpression.

Patient summary

These findings implicate low-molecular-weight protein tyrosine phosphatase as a novel oncogene in prostate cancer and could offer the possibility of using this protein as biomarker or target for treatment of this disease.

Take Home Message

We identified the low-molecular-weight protein tyrosine phosphatase (LMWPTP) as a new treatment target and predictive marker for clinical follow-up in prostate cancer (PCa). LMWPTP is overexpressed in PCa and results in a more malignant phenotype. Moreover, it is an independent prognostic predictor of poor clinical outcome.

Keywords: Biomarker, Metastasis, Phosphatases, Prostate cancer.

Footnotes

a Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

b Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil

c Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands

d Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands

e Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands

f Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

Corresponding author. Department of Gastroenterology and Hepatology, Erasmus Medical Center, Erasmus MC-University Medical Center, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. Tel. +31 10 7035821; Fax: +31 10 7031793.

* These authors share first authorship.

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