Roberta R Ruela-de-Sousa1, Elmer Hoekstra2, A Marije Hoogland3, Karla C Souza Queiroz4, Maikel P Peppelenbosch2, Andrew P Stubbs5, Karin Pelizzaro-Rocha6, Geert J L H van Leenders3, Guido Jenster7, Hiroshi Aoyama6, Carmen V Ferreira6, Gwenny M Fuhler8. 1. Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil. 2. Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. 3. Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. 4. Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil; Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 5. Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands. 6. Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil. 7. Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands. 8. Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: g.fuhler@erasmusmc.nl.
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.
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.
Authors: Alessandra V S Faria; Stefano P Clerici; Patricia F de Souza Oliveira; Karla C S Queiroz; Maikel P Peppelenbosch; Carmen V Ferreira-Halder Journal: Mol Cell Biochem Date: 2020-02-04 Impact factor: 3.842
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