Abstract 2666: Receptor protein tyrosine phosphatase type kappa is a prognostic marker, essential for regulating malignant behavior of glioma cells

Abstract

Abstract Malignant gliomas have a poor survival resulting from rapid growth of the tumor and extensive dispersion throughout the brain parenchyma. Discovery of tumor-specific biomarkers hold great promise in improving survival and thus call for better understanding of regulatory signals driving glioma cell migration and dispersal. Using genome-wide exploration, we have identified frequent genetic alterations at the Receptor protein tyrosine phosphatase type kappa (PTPRK) locus. These PTPRK alterations were among the top significant and very relevant to glioma biology since PTPRK is a dephosphorylation regulator of tyrosine phosphorylation (TP) signaling, a frequently altered signaling cascade in glioma as reported previously. Understanding PTPRK function will provide relevant novel insights into the molecular mechanisms underlying glioma cell growth and migration. PTPRK expression was analyzed by quantitative-RT-PCR and western blot. Mutations of PTPRK were identified by sequencing full length PTPRK transcripts from a subset of patients’ samples showing PTPRK loss of heterozygosity. Two major PTPRK variants were cloned and expressed in cells harboring altered PTPRK (U87MG cell line) to study their effect on PTPRK phosphatase activity and functionality. PTPRK locus undergoes allelic loss in glioma and contributes to cancer phenotype. It is an independent prognostic marker in glioma. Patients with altered PTPRK (23%) have shorter survival compared to those with normal PTPRK molecular status (p=0.001, Log-rank test, 14 vs. 30 months). PTPRK mRNA as well as protein levels were lower in tumor biopsies compared to non-tumor specimens. Mutational analysis revealed missense mutations in the phosphatase domain, resulting in altered PTPRK phosphatase activity, possibly due to changes in active site conformation. Further, PTPRK alterations changed expression profiles of the PTPRK protein as a result of altered post-translational processing. Reconstitution of PTPRK expression in glioma cells (U87MG cell line) harboring PTPRK deletions suppressed cell growth and migration which was alleviated by the PTPRK variants to differing extent. PTPRK knockdown via shRNA down-regulated its onco-suppressive function compared to PTPRK expressing cells. Our findings provide the first evidence of the key role of PTPRK expression in glioma and shed light on the biological consequences of mutations in the PTPRK gene which significantly alter PTPRK functionality. Biological relevance of PTPRK variants will be determined and validated on a large scale. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2666. doi:1538-7445.AM2012-2666