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Protein tyrosine phosphatase mRNA profiling reveals candidates impacting on glioma cell behavior.

Annika M. Bourgonje, Departments of Cell Biology Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Anna C. Navis, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Jan Schepens, Department of Cell Biology Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Kiek Verrijp, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Pieter Wesseling, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands and Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen; William P.J. Leenders, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen; Wiljan J.A.J. Hendriks Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands


Gliomas are tumors arising from glial cells that diffusely infiltrate the healthy brain parenchyma, making surgical resection and radiotherapy insufficiently effective. To improve patient outcome, new drug-modalities that target glioma growth and migration - hence likely impact on phosphotyrosine-based signaling processes - are desperately needed. We investigated the mRNA expression levels for 91 of the 109 protein tyrosine phosphatases (PTPs) in glioma tumor specimens using quantitative PCR and identified several PTPs that show differential expression between IDH1-wildtype and IDH1-mutated samples.
Findings confirmed enhanced expression levels for gene PTPRZ1 in different glioma subtypes. Lentivirus-mediated knock-down of PTPRZ1 in clinically relevant glioma cell models resulted in reduced migration and proliferation of glioma cells in vitro and also inhibited tumor growth in vivo. Whereas migration was regulated by the extracellular part of the PTPRZ-B isoform encoded by PTPRZ1, effects on proliferation depended on the intracellular C-terminal PDZ binding motif (Bourgonje et al., 2014).
We performed comparable studies on several other PTPs that display differential expression in glioma subtypes. These include three classical, tyrosine-specific PTPs, a dual-specificity PTP and a myotubularin-related PTP. Expression levels significantly correlate with patient survival probability, and lentivirus-mediated re-expression in xenograft-derived cell models markedly reduced proliferation and migration of glioma cells. Our findings underscore the importance of PTPs in the regulation of glioma cell behavior and may contribute to the identification of new entry points for drug therapies.

Reference: Bourgonje AM, Navis AC, Schepens JT, Verrijp K, Hovestad L, Hilhorst R, Harroch S, Wesseling P, Leenders WP, Hendriks WJ (2014) Intracellular and extracellular domains of protein tyrosine phosphatase PTPRZ-B differentially regulate glioma cell growth and motility. Oncotarget 5(18): 8690-8702.

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