Glioblastoma-associated Mesenchymal Stem Cells Promote Chemotherapeutic Resistance By Activating FOXS1-mediated Epithelial Mesenchymal Transition

Objective: The mechanism of tumor chemotherapy resistance caused by microenvironment of glioma is the focus of current research.Glioblastoma-associated mesenchymal stem cells(ga MSCs)are an important part of the tumor microenvironment.However,it is not clear whether ga MSCs affect glioma resistance to the commonly used chemotherapy drug temozolomide(TMZ).This study mainly discussed the effect of ga MSCs on chemotherapy resistance of glioma and related mechanisms.Methods: Human glioma cell lines U87 and glioma primary cells(GBM-1)cultured in ga MSCs conditioned medium and were treated with TMZ,proliferation ability was detected by cck-8,cell apoptosis was detected by flow analysis,and migration ability was detected by wound-healing assay.The effect of ga MSCs on gene expression in glioma cells was analyzed by gene microarray,and the expression of FOXS1 in glioma cells was analyzed by PCR and Western blot.Furthermore,lentivirus transfection was used to obtain glioma cells of knockdown or overexpressed FOXS1,and to detect changes of the EMT markers in glioma cells.At the same time,in situ models of nude mice were established with glioma cells under different conditions and treated with TMZ.The survival conditions of nude mice were observed and recorded.The tumor size was measured after 7weeks and the expression of Ki-67 in tumor tissues was detected by immunohistochemistry.Combined with the literature,the expression and secretion of IL-6in ga MSC were further analyzed by ELISA.IL-6 could up-regulate the expression of FOXS1 in glioma cells,and the blocking experiment could reverse the above effect.Results: ga MSCs promoted the proliferation,migration and chemotherapy resistance of glioma cells.This effect is closely related to the up-regulated expression of FOXS1 in glioma cells.FOXS1 functions by regulating the EMT process in tumor cells.Up-regulation or down-regulation of FOXS1 expression in cells resulted in corresponding changes in EMT process markers and chemotherapy resistance.Animal studies have also confirmed that ga MSCs promote chemotherapy resistance by up-regulating FOXS1 expression in glioma cells.Further experiments confirmed that ga MSCs mainly secreted IL-6 to act on glioma cells,and inhibition of IL-6 could reverse the up-regulation of FOXS1 expression.Meanwhile,IL-6 was mainly derived from ga MSCs subgroup with low CD90 expression.Conclusion: the ga MSCs subgroup with low CD90 expression can promote the expression of FOXS1 in glioma cells by secreting IL-6,thereby activating the process of epithelial mesenchymal transformation(EMT)of tumor cells and forming chemotherapeutic resistance to temozolomide.This study provides a new explanation for the mechanism of tumor cell chemotherapeutic resistance induced by glioma microenvironment.At the same time,it provides a new idea and target for further personalized treatment of glioma.