The Role And Mechanism Of TPX2 In Regulating The Proliferation And Metastasis Of Osteosarcoma

Background: Osteosarcoma,which is derived from primitive bone-forming mesenchymal cells,is ranked as the most common primary bone malignancy in children and adolescents worldwide.The prognosis of patients with osteosarcoma continues to be dismal;furthermore,the probability of metastasis of osteosarcoma is high,especially occurred in lung.Recently,more and more studies have shown that TPX2,as a potential oncogene,which is considered to be an important prognostic biomarker,is widely found to be expressed in a variety of tumors.However,little is known about the roles of TPX2 in the carcinogenis and meatstasis of osteosarcoma and it remains unclear whether TPX2 expression may associate with any clinicpathological features of osteosarcoma.Obejctive: To explore the role of TPX2 in regulating the proliferation and metastasis of osteosarcoma and the related mechanism.Methods:(1)Tissue array were used to detect TPX2 expression in 59 cases of osteosarcoma tissues,and the relationship between TPX2 and clinical characteristics of osteosarcoma patients was analyzed.(2)R2 database was to examine TPX2 m RNA expression with the metastasis-free survival probility in osteosarcoma patients.(3)The western blot was performed to detect the expression of TPX2 in human osteosarcoma cell lines.(4)To investigate the effect of TPX2 on the proliferation and metastasis of osteosarcoma in vitro and in vivo.(5)To investigate the potential mechanism of TPX2 in osteosarcoma through western blot and Co-IP assays.Results: The TPX2 gene is overexpressed in osteosarcoma and promotes cancer cell proliferation.TPX2 is an independent prognostic biomarker and associate with metastasis in osteosarcoma confirmed by independent patient cohorts.In this study,high expression of TPX2 associates with the activation of E2F1 signaling pathways in osteosarcoma,including Survivin,MMP9 and MMP13,which can stabilize the protein level of E2F1.Furthermore,the protein stability of E2F1 is regulated by a deubiquiting enzyme PSMD14.Meanwhile,endogeneous and exogeneous PSMD14 and E2F1 proteins specially interacts with each other which is regulated by the expression of TPX2.Upregulation of TPX2 in mouse xenograft models induced the activation of E2F1 signaling pathways,leading to accelerated tumor growth and metastasis in vivo.Conclusions: TPX2 is a driver of E2F1 signaing pathways through stabilizing the prtein level of E2F1 in osteosarcoma.Furthermore,our results collectively demonstrated that TPX2 might play a critical role for the carcinogenis and meatstasis of osteosarcoma and a promising therapeutic target for the treatment of osteosarcoma in the future.