The Roles Of PHB On The Regulation Of Glioma Stem Cell

Stem cells are defined as the cells with the capacities of extensive proliferation,self-renewal and multilineage differentiation.Recently,with the deeper exploration and recognition of tumor,the notion of cancer stem cell is gradually recognized by more and more researchers.Cancer stem cells(CSCs)are a small population of specific tumor cells,which possess not only the characters of tumor cells,such as tissue invasion and metastasis,but also the specificity of stem cells,such as self-renewal and differentiation potential.More and more studies reveal that despite aggressive therapy,the malignant tumors resistant to treatments and the patients have a dismal prognosis.One of the most important reasons is the existence of CSC,which might be the initiators of tumor.Aiming at CSCs and revealing the specificity and potential pathogenic mechanisms of CSCs will provide new strategies and experimental basis for the clinical treatment of malignant tumors.Glioma is the most common tumor of brain primary tumors.According to its pathological pattern,glioma can be divided into five different types,astrocytoma,medulloblastoma,glioblastoma multiforme(GBM),ependymocytoma and oligodendroglioma.GBM is of the most malignant glioma with a median survival of 12-15 months despite optimal therapy.Studies suggest that the glioma stem cells(GSC)attribute to the recurrence and the resistence to chemoradiotherapy.Identification of the characters of GSC might reveal the cause of tumor relapse and provide new thoughts for GBM clinical treatment.Recently,the studies on CSC mainly focus on identification of the marker of CSC,the epigenetic regulation of CSC and tumor microenvironment et al.Our lab devotes to study the function of specific highly expressed proteins in GSC and mechanism behind.We identified a series of differentially expressed proteins between GSCs and the matched non-stem tumor cells(NSTC)via mass spectrometry screen.Then,we analyzed the clinic relevance of those candidates by using the TCGA and other databases.Compared with the normal brain tissue,we found PHB specific highly expressed in the glioma and its expression level significantly correlated to the malignancy grade.However,in the other types of tumor,such as breast cancer,colon cancer,ovarian cancer,the expression level of PHB is relatively low or insignificant.Furthermore,we found that gliomas with high PHB expression have poor prognosis.These analysis indicated that PHB might contributes to glioma progression and regulates GSC.Firstly,we confirmed the screening and detected the preferentially expression of PHB in GSC compared to NSTC.Furthermore,we performed the PHB immunohistochemistry staining in a glioma tissue microarray and found that PHB is highly expressed in tumor cells compared with normal brain tissue.To investigate the effect of PHB on GSC,we employed the lenti-virus system to stably knock down PHB expression in both GSC and NSTC.The results reveal that the cell viability and selfrenewal of GSC were strongly inhibited by PHB knocked down.However,there was no obvious effects observed in PHB knocked-down NSTCs.In the orthotopic xenografts mouse model,we found that knocking down PHB strongly prolonged animal survival.In conclusion,our results suggested that PHB specific highly expressed in GSC at both protein and mRNA level.The expression of PHB correlated with the tumor malignancy grade and patients’ survival.Knocking down PHB significantly inhibited cell viability and self-renewal of GSCs,but not NSTCs,suggesting PHB plays a specific role in GSCs.Knocking down PHB increased survival of mice bearing GSCderived tumors.In further mechanism study,we found PHB located in the mitochondria of GSC and interacted with some mitochondrial proteins.In the following study,we will explore whether PHB influence the GSC mitochondria functions and what mechanism involved.We hope we can offer new clues and strategies for GBM and GSC clinical treatment.