4.3 Article

Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells

期刊

ONCOTARGET
卷 7, 期 34, 页码 54102-54119

出版社

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10851

关键词

MDA-9/Syntenin (SDCBP); stemness; glioma stem cells; survival; apoptosis

资金

  1. NIH [1 R01 CA134721]
  2. NCI Cancer Center Support Grant [P30 CA016059]
  3. VCU Massey Cancer Center developmental funds
  4. National Foundation for Cancer Research (NFCR)
  5. NIH-NINDS Center Core Grant [5 P30 NS047463]
  6. NIH-NCI Cancer Center Support Grant [P30 CA016059]

向作者/读者索取更多资源

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.

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