Abstract
Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs. Consequently, there is a pressing need to identify therapeutic targets and novel options to effectively target this therapy-resistant cell population. The precise roles of GSCs in governing GBM development, progression and prognosis are under intense scrutiny, but key upstream regulatory genes remain speculative. MDA-9/Syntenin (SDCBP), a scaffold protein, regulates tumor pathogenesis in multiple cancers. Highly aggressive cancers like GBM express elevated levels of MDA-9 and contain increased populations of GSCs. We now uncover a unique function of MDA-9 as a facilitator and determinant of glioma stemness and survival. Mechanistically, MDA-9 regulates multiple stemness genes (Nanog, Oct4 and Sox2) through activation of STAT3. MDA-9 controls survival of GSCs by activating the NOTCH1 pathway through phospho-Src and DLL1. Once activated, cleaved NOTCH1 regulates C-Myc expression through RBPJK, thereby facilitating GSC growth and proliferation. Knockdown of MDA-9 affects the NOTCH1/C-Myc and p-STAT3/Nanog pathways causing a loss of stemness and initiation of apoptosis in GSCs. Our data uncover a previously unidentified relationship between MDA-9 and GSCs, reinforcing relevance of this gene as a potential therapeutic target in GBM.
Highlights
Cancer is multifactorial in its etiology and multistep in its evolution [1]
Our studies demonstrate for the first time that MDA-9 promotes glioma stem cell phenotypes and survival through regulation of NOTCH1, C-Myc, STAT3 and Nanog in glioma stem cells (GSCs)
In shmda-9 GSCs, expression of miR-221 was significantly decreased (Figure 8A). These findings demonstrate that p27/kip-1 is regulated by mda-9 through c-myc and miR-221. mda-9 kd caused decreased cIAP2 expression (Figure S2) and this combined with increased expression of p27/kip-1 in shmda-9 GSCs may amplify GSC death
Summary
Cancer is multifactorial in its etiology and multistep in its evolution [1]. Glioblastoma multiforme (GBM), the most common form of primary brain tumor, is an aggressive cancer that causes high mortality and morbidity. In addition to cell surface markers, several pathways and molecules that control self-renewal and differentiation of cancer stem cells and normal stem cells have been identified including p-STAT3, NOTCH, C-Myc, NANOG, OCT4, SOX2 and others [3, 15, 16]. These regulators of stemness influence tumorigenesis and tumor progression [17]. Our studies demonstrate for the first time that MDA-9 promotes glioma stem cell phenotypes and survival through regulation of NOTCH1, C-Myc, STAT3 and Nanog in GSCs
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