Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in ...Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.展开更多
Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We de...Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We demon- strated that CA1P also showed an outstanding anti-cancer effect on hepatocellular carcinoma （HCC） in vivo and in vitro. As determined by DCFH-DA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the down-regulation of Mcl-1. Additonal western blot and immunofluorescence assays further indi- cated that CA1P inhibited Wnt/β-catenin pathway through GSK-3β activition with an increasing of Mcl phosphoryl- ation and subsequent degradation mediated by tubulin-dynactin p l50-AKT signaling pathway axis. Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK-3β inhibitor （ CHIR-99021 ）. Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage （TAM） apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGF-β were also altered. Adoptive transfer of macrophages reinstated tumor growth treated by CA1P. These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel anti-HCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment. The findings would be beneficial for exploring new application of anti-microtubu- lar drugs on oncotherapy.展开更多
基金This work was supported by the National Natural Science Foundation(82172594 and 82373046)the Hunan Graduate Research Innovation Project(CX20230318),China.
文摘Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.
文摘Combretastatin A-1 phosphate （CA1P） is a tubulin polymerization inhibitor that binds to the colchicine- binding site of tubulin and shows potential anti-tumor activity to acute myelocytic leukemia as reported. We demon- strated that CA1P also showed an outstanding anti-cancer effect on hepatocellular carcinoma （HCC） in vivo and in vitro. As determined by DCFH-DA dye and Western blot, CA1P induced ROS accumulation and apoptosis in HepG2 cells with the down-regulation of Mcl-1. Additonal western blot and immunofluorescence assays further indi- cated that CA1P inhibited Wnt/β-catenin pathway through GSK-3β activition with an increasing of Mcl phosphoryl- ation and subsequent degradation mediated by tubulin-dynactin p l50-AKT signaling pathway axis. Apoptosis of HepG2 cells induced by CA1P was reversed by the GSK-3β inhibitor （ CHIR-99021 ）. Furthermore, determined by immunohistochemistry of an orthotopic HCC tumor model, CA1P showed a significantly effect on tumor associated macrophage （TAM） apoptosis in vitro and eliminated TAM in tumor microenviroment in vivo, while the infiltration of Treg cells and expression of TGF-β were also altered. Adoptive transfer of macrophages reinstated tumor growth treated by CA1P. These results indicated that CA1P presented potent potential on the regulation of hepatocellular carcinoma cells and TAMs, and also revealed a novel anti-HCC mechanism of CA1P, which acted on both cancer cells and tumor microenvironment. The findings would be beneficial for exploring new application of anti-microtubu- lar drugs on oncotherapy.
