gms | German Medical Science

67th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Korean Neurosurgical Society (KNS)

German Society of Neurosurgery (DGNC)

12 - 15 June 2016, Frankfurt am Main

PRG3 amplifies Ras-dependent oncogenesis in brain tumors

Meeting Abstract

  • Nicolai E. Savaskan - Neurochirurgische Klinik, Universitätsklinikum Erlangen, Germany
  • Zheng Fan - Neurochirurgische Klinik, Universitätsklinikum Erlangen, Germany
  • Thomas Broggini - Neurochirurgische Klinik, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Germany
  • Michael Buchfelder - Neurochirurgische Klinik, Universitätsklinikum Erlangen, Germany
  • Ilker Y. Eyupoglu - Neurochirurgische Klinik, Universitätsklinikum Erlangen, Germany

Deutsche Gesellschaft für Neurochirurgie. 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS). Frankfurt am Main, 12.-15.06.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocP 036

doi: 10.3205/16dgnc411, urn:nbn:de:0183-16dgnc4113

Published: June 8, 2016

© 2016 Savaskan et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: Malignant gliomas are one of the most devastating primary brain tumors in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and altered gene expression levels conferring selective growth advantage.

Method: Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic transformation in gliomas.

Results: We have identified perturbed PRG3 levels in human brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. We hypothesized that imbalances of PRG3 levels bear the capacity to transform cells by facilitating similar downstream effects. To test this we analyzed wild-type gliomas and gliomas with distinct PRG3 levels. Perturbation of PRG3 levels in glioma cells accelerates anchor-independent proliferation and migration, indicating amplified oncogenic signaling. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome, whereas tumor angiogenesis remained unaffected. Hence, PRG3 interacts with RasGEF1 and activates oncogenic Ras and disrupts the lipid second messenger phosphatidylinositol-(4,5)-bisphosphate (PIP2) from the plasma membrane. Restoration of PIP2 levels via phosphatidylinositol 4-phosphate 5-kinase (PIP5K) attenuated PRG3-induced transformation and reverted the phenotype.

Conclusions: In conclusion, these results show that PRG3 acts context-dependent in brain cells, and interference with the PRG3 homeostasis amplifies oncogenic signaling events.