PRG3 induces Ras-dependent oncogenic cooperation in gliomas
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Zheng Fan1,*, Philipp Bittermann-Rummel1,*, Eduard Yakubov1,2, Daishi Chen1, Thomas Broggini3, Tina Sehm1, Gökce Hatipoglu Majernik1, Stefan W. Hock1, Marc Schwarz1,4, Tobias Engelhorn4, Arnd Doerfler4, Michael Buchfelder1, Ilker Y. Eyupoglu1,#, Nicolai E. Savaskan1,5,#
1Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany
2Department of Neurosurgery, Klinikum Nürnberg, Paracelsus Medical University, Nürnberg, Germany
3Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
4Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen–Nürnberg, Erlangen, Germany
5BiMECON ENT., Berlin-Brandenburg, Germany
*These authors contributed equally to this work
#These authors contributed equally as senior authors to this study
Keywords: glioma, PRG3, Ras, oncogenesis, neuronal plasticity
Received: October 22, 2015 Accepted: March 10, 2016 Published: April 05, 2016
Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas.
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