Abstract
Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) with <10% 5-year survival rate. The growth and invasion of GBM cells into normal brain make the resection and treatment difficult. A better understanding of the biology of GBM cells is crucial to the targeted therapies for the disease. In this study, we identified Septin9 (SEPT9) and Septin2 (SEPT2) as GBM-related genes through integrated multi-omics analysis across independent transcriptomic and proteomic studies. Further studies revealed that expression of SEPT9 and SEPT2 was elevated in glioma tissues and cell lines (A172, U87-MG). Knockdown of SEPT9 and SEPT2 in A172/U87-MG was able to inhibit GBM cell proliferation and arrest cell cycle progression in the S phase in a synergistic mechanism. Moreover, suppression of SEPT9 and SEPT2 decreased the GBM cell invasive capability and significantly impaired the growth of glioma xenografts in nude mice. Furthermore, the decrease in GBM cell growth caused by SEPT9 and SEPT2 RNAi appears to involve two parallel signaling pathway including the p53/p21 axis and MEK/ERK activation. Together, our integration of multi-omics analysis has revealed previously unrecognized synergistic role of SEPT9 and SEPT2 in GBM, and provided novel insights into the targeted therapy of GBM.
Highlights
Glioblastoma (GBM), which starts in the brain and spine with approximately 210,000 new diagnoses per year around the world[1], account for 81% of primary malignant brain tumors[2]
We filtered the candidates through a list of proteins derived from proteomic profiling of three different GBM cell lines, and further narrowed down SEPT9, SEPT2, WEE1, RPN2, and others as the final candidates (Fig. 1)
We chose SEPT9 and SEPT2 for further validation as Septins have been implicated in cell proliferation, migration, and tumorgenesis but their roles in GBM have not been determined
Summary
Glioblastoma (GBM), which starts in the brain and spine with approximately 210,000 new diagnoses per year around the world[1], account for 81% of primary malignant brain tumors[2] According to their origins, there are three types of gliomas including astrocytic tumors (World Health Organization classification astrocytoma grades I, II (astrocytoma), III (anaplastic astrocytoma), and IV (GBM)), oligodendrogliomas, ependymomas, and mixed gliomas[3]. There is a strong rationale for developing multi-target therapies for GBM14,15 In light of these considerations, we applied an unbiased multi-omics method for integrating results from microarray multiplex analysis and proteomic identification analysis. This combinatory approach revealed two novel GBM-related molecules, Septin[9] (SEPT9) and Septin[2] (SEPT2)
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