Abstract
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20–21 months. Recent knowledge suggests that its recurrence is in part due to the presence of cancer stem cells (CSCs), which display radioresistant, chemoresistant, self-renewal and tumorigenic potential. Enhancers of Zeste 2 (EZH2) and AXL receptor tyrosine kinase (AXL) are both highly expressed in GBM. Additionally, they are an essential regulator involved in CSCs maintenance, migration, invasion, epithelial-to-mesenchymal transition (EMT), stemness, metastasis and patient survival. In this study, we used a small molecule, n-butylidenephthalide (BP), to assess the anti-GBM stem-like cells potential, and then tried to find out the associated genes involved with regulation in migration and invasion. We demonstrated that BP reduced the expression of AXL and stemness related genes in a dose-dependent manner. The migratory and invasive capabilities of GBM stem-like cells could be reduced by AXL/EZH2. Finally, in the overexpression of AXL, EZH2 and Sox2 by transfection in GBM stem-like cells, we found that AXL/EZH2/TGF-β1, but not Sox2, might be a key regulator in tumor invasion, migration and EMT. These results might help in the development of a new anticancer compound and can be a target for treating GBM.
Highlights
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor in the world
We demonstrated that a novel small molecule, BP, inhibited tumor migration and invasion by downregulating AXL, and reducing epithelial-to-mesenchymal transition (EMT) [41] in GBM
We further evaluated the efficacy of BP for treating GBM stem-like cells (CD133 high expression cells), and assessed the inhibition of migration and invasion
Summary
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor in the world. Some scientists think that cancer stem cells (CSCs) are a small subset of cells within a tumor that initiate both the primary disease and its recurrence because of their capacity for self-renewal and inherent chemoresistance, radioresistance, migration and invasion [4,5,6,7,8]. The GBM stem-like cells 1XM (high CD133+, radioresistant) and 0XM (low CD133+, parental) were kindly given by Dueng-Yuan Hueng. Our recent study was focused on developing a local drug delivery polymer-BP wafer in which BP was incorporated into a biodegradable polyanhydride material called CPP-SA The results of both subcutaneous and intracranial implantation of BP wafers revealed that BP wafers significantly reduced tumor size in xenograft, orthotopic, and spontaneous brain tumors in transgenic mice [40]. TTThhheee sssccchheemmaattiicc mmeecchhaannniiisssmmmooofffBBBPPPttrtrereeaaatmttmmeeennntttiniinnGGGBBBMMMceccleelsllll.ssB.. lBBollcookcckkaraarrorrrwoowswss ↙↙: P::aPPtahattwhhwawyaa;yyT;; bTTabbrsaarr⊥ss: ⊥⊥In::hibIInnithhioiibbniitttiihooenngettnhhee exggpeernneeessieoexxnpp; rrGeerssassiyioonun;p; wGGarrraadyys aururppowwwaasrr↑dd:ssInaacrrrerooawwsessth↑e↑::phIInennccrroeemaasseeenotnthh;eeGrppayhheednnooowmmneewnnooanrnd;; GGarrraaoyywddsoo↓ww: nnDwweacarreddaasaerrrrtoohwwe ssp↓↓h::eDDnoeemccrreeanassoeentt.hhee pphheennoommeennoonn
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