Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling.

Abstract

Epidermal growth factor receptor (EGFR)-Akt signaling cascade activation plays a pivotal role in gliomas malignant phenotype, especially in Classical and Mesenchymal subtype gliomas. However, the molecules and mechanisms underlying regulate and maintain the activation of EGFR-AKT signaling remains unclear. Previously reports showed that DIRAS3 inhibits cell proliferation and induces autophagy in ovarian, breast, lung and prostate cancers, which is heterozygosity loss or down-regulated in aforementioned cancers and functionally as a tumor suppressor, whereas the role of DIRAS3 in glioma is still veiled. Here, in this study, we investigated the biological function and role of DIRAS3 in gliomas, and found that DIRAS3 is up-regulated in gliomas and is positively correlated with poor prognosis of glioma patients, meanwhile, over-expressed DIRAS3 promotes glioma cells proliferation and invasion. Further mechanistic study showed that the expression level of DIRAS3 in Classical and Mesenchymal subtype GBMs is higher, and over-expression of DIRAS3 promotes EGFR-AKT signaling activation at the downstream of EGFR and increases AKT phosphorylation, meanwhile suppression of AKT by MK-2206 reverses the tumor promoting function of DIRAS3. Taken together, these findings reveal a novel oncogenic role of DIRAS3 in the development and progression of glioma, which suggest that DIRAS3 could serve as a potential diagnostic marker and a promising therapeutic target of gliomas.

• Authors: Yong Peng, Jiaoying Jia, Zhongzhong Jiang, Dezhi Huang, Yugang Jiang, Yun Li
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 505 Issue 2 Pg. 413-418 (10 28 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 30266404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• DIRAS3 protein, human
• Neoplasm Proteins
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• rho GTP-Binding Proteins

Topics

• Autophagy (drug effects)
• Cell Proliferation (drug effects)
• ErbB Receptors (metabolism)
• Glioma (etiology, metabolism)
• Humans
• Neoplasm Proteins (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• rho GTP-Binding Proteins (pharmacology)