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

• Published in: European urology 2016-04, Vol.69 (4), p.710-719
• Main Authors: Ruela-de-Sousa, Roberta R, Hoekstra, Elmer, Hoogland, A. Marije, Souza Queiroz, Karla C, Peppelenbosch, Maikel P, Stubbs, Andrew P, Pelizzaro-Rocha, Karin, van Leenders, Geert J.L.H, Jenster, Guido, Aoyama, Hiroshi, Ferreira, Carmen V, Fuhler, Gwenny M
• Format: Article
• Language: English
• Subjects: Aged; Anoikis; Biomarker; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chi-Square Distribution; Focal Adhesion Kinase 1 - metabolism; Humans; Kaplan-Meier Estimate; Male; Metastasis; Middle Aged; Molecular Weight; Multivariate Analysis; Neoplasm Metastasis; Neoplasm Recurrence, Local; Patient Selection; Paxillin - metabolism; Phosphatases; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prostate cancer; Prostatectomy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Risk Assessment; Risk Factors; Time Factors; Tissue Array Analysis; Transfection; Up-Regulation; Urology; Watchful Waiting
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2015.06.040

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.