The Role Of TAZ In Glioblastoma Cell Proliferation And Tumorigenecity

In this study,to examin the role and mechanism of TAZ in glioblastoma,we first analyzed the TAZ expression.TAZ(transcriptional co-activator with a WW domain)is a downstream transcriptional coactivator in Hippo pathway.TAZ is not a transcription factor because of lacking a DNA-binding domain,while TAZ could serve as a transcriptional regulator via its intrinsic transactivation domain.It is reports that TAZ is closely related to cell proliferation of cancer,and the expression of TAZ is elevated in multiple human cancers,such as invasive ductal breast cancer and glioblastoma.The cell cycle progression usually regulates cell proferation.EGFR is a member of ErbB family,which is activated by phosphorylating the tyrosine kinase moiety.Following EGFR activation,three major intracellular signaling pathways are activated,including the PI3K/AKT kinase pathway,the Ras-ERK cascade,and the STAT3 dependent signaling events.TAZ can promote MCF10 A cells proliferation independent of EGF via promoting the expression of AREG.It is reports that TAZ is closely related to cell proliferation of cancer.However,the role of TAZ in regulating cell proliferation and tumor formation in glioblastoma cells has not been explored.We first evaluated the clinical significance of TAZ in a large cohort of GBM patients and found a negative association of TAZ expression with overall survival.Furthermore,we found that TAZ protein levels were significantly elevated in the tumor tissue over normal in GBM sample,suggesting that TAZ may promote the development and progression of GBM.Subsequently,through shRNA knockdown or stable plasmid transfection,the TAZ protein level was found to be positively related to the proliferation of GBM cells.Tumor xenograft experiments in nude mice indicated that TAZ significantly promoted glioma growth in vivo.Moreover,immunostaining assays revealed that tumor tissues formed by TAZ-overexpressing cells had much stronger Ki67 expression,suggesting that TAZ promoted the tumor formation of GBM cells by accelerating cell proliferation.Furthermore,a cell cycle analysis by FACS revealed that increased TAZ expression resulted in a significant decrease in the percentage of G0/G1 phase cells,suggesting that TAZ accelerates the cell cycle in GBM cells.All of our findings together indicate that TAZ functions to promote the development and progression of GBM.In the present study,TAZ was found to potentiated EGFR and its downstream signaling pathways activation in GBM cells and xenograft tumors.These results suggest that TAZ activate EGFR pathway in GBM cells.Blockage with Erlotinib,an inhibitor of EGFR activation,resulted in a significant inhibition of the GBM cell proliferation induced by TAZ,suggesting that TAZ promotes GBM cell proliferation via activation of EGFR pathway.