title: PRG3 induces Ras-dependent oncogenic cooperation in gliomas.
abstract: 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.
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Bittermann-Rummel
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.|Department of Neurosurgery, Klinikum Nürnberg, Paracelsus Medical University, Nürnberg, Germany.
authors.forename: Eduard
authors.initials: E
authors.lastname: Yakubov
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Daishi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Broggini
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Sehm
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Gökce
authors.initials: G
authors.lastname: Hatipoglu Majernik
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Hock
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.|Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engelhorn
authors.affiliation: Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arnd
authors.initials: A
authors.lastname: Doerfler
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Ilker Y
authors.initials: IY
authors.lastname: Eyupoglu
authors.affiliation: Translational Neurooncology Laboratory, Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.|BiMECON ENT., Berlin-Brandenburg, Germany.
authors.forename: Nicolai E
authors.initials: NE
authors.lastname: Savaskan
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D020666:ras-GRF1 / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; D020666:ras-GRF1; C486235:PLPPR1 protein, human; D010744:Phosphoric Monoester Hydrolases
keywords: PRG3; Ras; glioma; neuronal plasticity; oncogenesis