| Background and objective:Glioma is a common primary tumor of the central nervous system,which is characterized by high degree of malignancy,treatment difficulty,poor prognosis and frequent recurrence.The standard therapy of glioma is a complex treatment with surgical resection of tumors and adjuvant therapy such as radiotherapy and chemotherapy.Although the diagnosis and treatment technology of glioma has been continuously improved and progressed,the current status of the treatment of glioma is still not optimistic.Glioma cells has a high ability of migration and invasion,which often causes extensive invasion of tumor cells and brings great difficulties to the treatment of glioma.Therefore,investigating targeted medicine and discussing the proper molecular mechanism causing this high migratory and invasive ability of glioma cells are pivotal problems to be solved.Recently,a large body of evidence indicates that epithelial to mesenchymal transition(EMT)has much to do with the invasion,metastasis and progression of tumors.EMT may be the key biological process during tumor invasion and metastasis in which leads to increased tumor cell migratory and invasive abilities.Moreover,EMT is also closely correlated with cancer stem cells(CSCs),which is also the major cause of tumor invasion,metastasis,drug resistance and relapse.Therefore,if we can find a proper method of targeting EMT in glioma,it may not only inhibit EMT,but also regulate cancer stem cell properties in glioma cells,which will undoubtedly bring new breakthroughs in the treatment of glioma.Metformin is a widely used hypoglycemic agent and resveratrol is a natural polyphenol compound.Recent studies have suggested that metformin and resveratrol not only exert an antitumor effect,but also,more importantly,regulate the EMT process of tumor cells.However,the effects of these two drugs on the regulation of EMT in glioma have not been systematically studied.The present study aimed to explore the occurrence of EMT in glioma cells,and to investigate the role and mechanism of metformin and resveratrol as an intervention drug in inhibiting EMT in glioma.Methods:In the present study,we used TGF-?1 as a tool to induce EMT in glioma cells in order to explore the effect of EMT on biological function of glioma cells.We used metformin and resveratrol as an intervention drug for EMT in glioma.By using western blotting,wound healing assay,Transwell invasion assay and tumor sphere formation assay,we analyzed and studied the regulatory effect of metformin and resveratrol on EMT and EMT-induced cancer stem cell properties in glioma,and explored the potential mechanism.Results:1.TGF-?1 induced the transformation of EMT markers in glioma cells,and transformed glioma cells into a more stretched and elongated morphology,and promoted the migratory and invasive ability of glioma cells,indicating that TGF-?1 induced EMT and established EMT model in glioma cells.2.Interfering the expression of transcription factor ZEB1 inhibited the transformation of EMT markers and inhibited migratory and invasive ability in glioma cells,thereby inhibiting EMT in glioma cells.3.The occurrence of EMT increased the self-renewal ability of glioma cells and upregulated the expression of cancer stem cell markers,indicating that EMT induced cancer stem cell properties in glioma cells.4.Metformin and resveratrol inhibited the expression of EMT markers and inhibited the migration and invasion of glioma cells,thereby inhibiting the occurrence of EMT in glioma cells.5.Metformin and resveratrol inhibited EMT in glioma cells by inhibiting AKT/m TOR pathway and Smad-dependent pathway,respectively.6.Metformin and resveratrol inhibited EMT-induced self-renewal ability and the expression of cancer stem cell markers,indicating that metformin and resveratrol inhibited EMT-induced cancer stem cell properties in glioma cells.Conclusions:1.EMT can be induced in LN18 and U87 glioma cells under certain condition.2.ZEB1 plays a pivotal role in regulating EMT in glioma cells.3.EMT can induce the formation of GSCs and stem cell properties in glioma cells4.Metformin and resveratrol can inhibit EMT,migration and invasion in glioma cells.5.Metformin and resveratrol inhibit EMT in glioma cells by inhibiting AKT/m TOR pathway and Smad-dependent pathway,respectively.6.Metformin and resveratrol can inhibit EMT-induced cancer stem cell properties in glioma cells... |
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