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Oncotarget: PRG3 induces Ras-dependent oncogenic cooperation in gliomas


FOR IMMEDIATE RELEASE
2020-12-03

Here is a link to a video interview with Dr. Nicolai E. Savaskan about this research on the Oncotarget YouTube Channel

Oncotarget published "PRG3 induces Ras-dependent oncogenic cooperation in gliomas" which reported on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas.

The researchers 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, undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 inhibits Ras.

Thus, the Oncotarget author's data show that the interference with PRG3 homeostasis amplifies oncogenic properties and fosters the malignancy potential in gliomas.

The Oncotarget author's data show that the interference with PRG3 homeostasis amplifies oncogenic properties and fosters the malignancy potential in gliomas

Dr. Nicolai E. Savaskan from The Friedrich-Alexander University of Erlangen-Nürnberg (FAU) as well as BiMECON ENT. said, "Malignant gliomas are one of the most common primary brain tumor entities with an annual incidence rate of 5.8 in the USA and in Europe."

Recently, progress has been made in the characterization of malignant gliomas revealing various heterogeneous genetic lesions with the potential to transform glial progenitor cells and differentiated glial cells into malignant gliomas.

In malignant gliomas PRG3 is expressed in opposing amounts in the way that PRG3 is either elevated or down-regulated compared to non-transformed human specimens.

Analysis of the human expression databases does at least show that a deregulated expression dosage of PRG3 leads to a worse outcome in patients with malignant gliomas.

Deregulated PRG3 expression reduced apoptosis, enhanced proliferation, migration and thus elevated the malignancy of glioma cells.

Figure 6: Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. (A) Left, PRG3 interacts with RasGEF1. Cells were transfected with either flag-tagged PRG3 plus RasGEF1, solely RasGEF1 or mock vector and immunoprecipitated for PRG3. Right, immunoblots of total lysates (TL) are shown for RasGEF1 and PRG3 expression controls. (B) PRG3 interacts with RasGEF1 in vivo. Left panel shows endogenous PRG3/RasGEF1 complex detected by immunoprecipitation with various PRG3 antibodies in different brain tissue samples (hippocampus). Right panel shows endogenous PRG3/RasGEF1 complex detected by immunoprecipitation with RasGEF1. (C) PRG3 and PRG3kd glioma cells response differently to Ras inhibitors. Quantitative analysis of cell growth revealed that Ras inhibitor manumycin (5 μM) and salirasib (20 μM) inhibit PRG3 glioma cell growth by 86% and 30% respectively, while reduced PRG3kd gliomas proliferation by 64% and 14% respectively. Non-treated control of each cell types (con) were set as 100% and given in black. Statistical significance was calculated with Student's t-test (mean ± SD, n = 8 per group; *P < 0.05). (D) PRG3 glioma cells response differently to dominant negative Ras (RasN17) compared to wild type (WT) and PRGkd gliomas. Quantitative analysis of cell growth revealed that dominant negative Ras inhibits PRG3 glioma cell growth by 28% whereas PRG3kd gliomas and WT gliomas are less sensitive. Non-treated control of each cell types (con) were set as 100% and given in black. Statistical significance was calculated with Student's t-test (mean ± SD, n = 8 per group; *P < 0.05). (E) PRG3 signaling domains and downstream consequences. Summary of PRG3 signaling domains and their effects on Ras activation. Full length PRG3 is a multidomain protein possessing an intracellular C-terminal tail interacting with the guanine nucleotide exchange factor RasGEF1 (blue circle). The integral membrane domain of PRG3 is proposed to decrease Ras activation.

Further investigations of the underlying signaling pathway revealed that PRG3 interacts with RasGEF1. Thus, interference with the regulation and homeostasis of PRG3 amplifies malignancy in glioma cells.

The Savaskan Research Team concluded in their Oncotarget Research Paper that the significance of deranged PRG3 levels is reflected by the response rates to therapeutic small molecule inhibitors.

Thus, gliomas with high PRG3 levels are prone to Ras blockers and their tumor growth can be treated with Ras-inhibiting drugs such as salirasib.

Future studies will unravel whether other kinases are affected by PRG3, and if so in which hierarchy the downstream targets affect cell growth.

Altogether, the authors provide evidence that PRG3 acts dosage and context-dependent in the nervous system, and interference with its balanced level can cooperate in oncogenic signaling.

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DOI - https://doi.org/10.18632/oncotarget.8592

Full text - https://www.oncotarget.com/article/8592/text/

Correspondence to - Nicolai E. Savaskan - savaskan@gmx.net, nic.savaskan@gmail.com

Keywords - glioma, PRG3, Ras, oncogenesis, neuronal plasticity

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