Abstract
BackgroundOsteosarcoma is the most common bone malignancy in children and adolescents, and 20%–30% of the patients suffer from poor prognosis because of individual chemoresistance. The Hippo/yes-associated protein (YAP) signaling pathway has been shown to play a role in tumor chemoresistance, but no previous report has focused on its involvement in osteosarcoma chemoresistance. This study aimed to investigate the role of the Hippo/YAP signaling pathway in osteosarcoma chemoresistance and to determine potential treatment targets.MethodsUsing the Cell Titer-Glo Luminescent cell viability assay and flow cytometry analysis, we determined the proliferation and chemosensitivity of YAP-overexpressing and YAP-knockdown osteosarcoma cells. In addition, using western blotting and the real-time polymerase chain reaction technique, we investigated the alteration of the Hippo/YAP signaling pathway in osteosarcoma cells treated with chemotherapeutic agents.ResultsMammalian sterile 20-like kinase 1 (MST1) degradation was increased, and large tumor suppressor kinase 1/2 (LATS1/2) total protein levels were decreased by methotrexate and doxorubicin, which increased activation and nuclear translocation of YAP. Moreover, YAP increased the proliferation and chemoresistance of MG63 cells.ConclusionsThe Hippo/YAP signaling pathway plays a role in osteosarcoma chemoresistance, and YAP is a potential target for reducing chemoresistance.
Highlights
Osteosarcoma is the most common bone malignancy in children and adolescents, and 20%–30% of the patients suffer from poor prognosis because of individual chemoresistance
YAP regulated the proliferation and chemoresistance of osteosarcoma cells To investigate the function of the Hippo/YAP pathway in osteosarcoma chemoresistance, we successfully established stable YAP-overexpressing and YAP-knockdown MG63 cell lines by retrovirus and lentiviral infection
Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining and flow cytometry analysis confirmed the protective function of YAP in response to methotrexate (20 mM) or doxorubicin (10 μM), as the apoptosis of YAPoverexpressing cells was significantly lower than that of the control (P = 0.001 and P = 0.043, respectively)
Summary
Osteosarcoma is the most common bone malignancy in children and adolescents, and 20%–30% of the patients suffer from poor prognosis because of individual chemoresistance. The Hippo/yes-associated protein (YAP) signaling pathway has been shown to play a role in tumor chemoresistance, but no previous report has focused on its involvement in osteosarcoma chemoresistance. This study aimed to investigate the role of the Hippo/YAP sign‐ aling pathway in osteosarcoma chemoresistance and to determine potential treatment targets. Osteosarcoma is the most common bone malignancy in children and adolescents. The consensus is that poor chemotherapeutic effect on some patients is the primary obstacle to a higher survival rate of osteosarcoma patients [2]. Methotrexate and doxorubicin are the most commonly used drugs for the treatment of osteosarcoma, and resistance to them substantially decreases patients’ survival rates.
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