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
Aim Retinoic acid receptor alpha （RARα） plays a critical role in the differentiation process of osteo- sarcoma cells induced by all-trans retinoic acid （ATRA）. However, degradation of RARoL through ubiquitin pro-...Aim Retinoic acid receptor alpha （RARα） plays a critical role in the differentiation process of osteo- sarcoma cells induced by all-trans retinoic acid （ATRA）. However, degradation of RARoL through ubiquitin pro- teasome pathway weakens the differentiation efficiency of osteosarcoma cells. Therefore, it is necessary to explore the regulatory mechanisms involved in RARoL degradation. Methods U2OS cells were mainly used as our research models. （1） Protein levels were detected by Western blot; （2） The interactions between MDM2 and RARalpha were determined by immunofluorescence and immunoprecipitation; （3） Related proteins and genes were investiga- ted via transfection; （4） The expression levels of MDM2 and OPN in patient biopsies were detected by immunohis- tochemistry; （5） Alkaline phosphatase activity was assessed by colorimetric assays using the BCIP/NBT Alkaline Phosphatase Color Development kit. Results In this report, it demonstrated that interaction with MDM2 leaded to strong stimulation of RARoL polyubiquitination and degradation by proteasomes. MDM2 appeared to function as an ubiquitin E3 ligase in this process, since the MDM2 RING domain mutant inhibited the ubiquitination of RARoL. Furthermore, MDM2 was capable of stimulating RARoL polyubiquitination under cell-free conditions. Moreover, it also provided evidence that silencing or inhibiting MDM2 promotes the differentiation of U2OS cells as induced by ATRA. Conclusions MDM2 serves as an E3 ubiquitin ligase to regulate the degradation of RARoL and becomes a novel therapeutic target for ATRA-based differentiation therapeutic approaches in osteosarcoma.展开更多
Background and objective Osteosarcoma is a high-malignant bone tumor and is the most frequent malignant bone tumor in children and adolescents. Significant proportions of the
骨肉瘤(osteosarcoma,OS)是最常见的原发性骨恶性肿瘤,具有很高的局部浸润和转移倾向。c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNK)是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族中极为重要的一员,而且JNK信...骨肉瘤(osteosarcoma,OS)是最常见的原发性骨恶性肿瘤,具有很高的局部浸润和转移倾向。c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNK)是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族中极为重要的一员,而且JNK信号通路已被证明参与调控了OS的发生发展。该文就JNK信号通路调控OS的增殖、迁移、侵袭、血管生成、自噬、凋亡和焦亡等生物学行为,以及氧化应激和非编码RNA通过JNK信号通路对OS调控的研究进展进行综述,进一步探究JNK信号通路的内在调控机制,为寻找OS的治疗提供新的思路。展开更多
骨肉瘤(osteosarcoma,OS)是骨组织常见的原发性恶性肿瘤,具有较高的病死率、致残率、转移率和复发率,其发病机制复杂,严重影响患者的生活质量,给家庭和社会都带来了巨大的经济负担。中药具有“多靶点、多成分、多途径”的特点,近年来,...骨肉瘤(osteosarcoma,OS)是骨组织常见的原发性恶性肿瘤,具有较高的病死率、致残率、转移率和复发率,其发病机制复杂,严重影响患者的生活质量,给家庭和社会都带来了巨大的经济负担。中药具有“多靶点、多成分、多途径”的特点,近年来,大量动物或细胞模型实验研究发现,OS发生进展的作用机制与神经源性位点缺口同源蛋白(neurogenic locus notch homolog protein,Notch)、有丝分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、分泌型糖蛋白(Wingless/Integrated,Wnt)/β-连环蛋白(beta-catenin,β-catenin)、磷酸酰肌醇3-激酶(phosphatidylinositol-3-kinases,PI3K)/蛋白质激酶B(protein kinase B,AKT)、刺猬因子(Hedgehog,Hh)、核转录因子(nuclear factor kappa-B,NF-κB)、转化生长因子-β(transforming growth factor-β,TGF-β)/果蝇抗蜕皮蛋白同源物(small mothers against decapentaplegic,Smad)、信号转导及转录激活因子(signal transdueer and activator of tanseription,STAT)通路紧密相关,中药可通过干预以上相关信号通路从而影响细胞增殖、迁移、侵袭、凋亡和自噬等生物学过程发挥抗肿瘤的作用。本研究以细胞信号通路为基础,阐述了上述信号通路在OS中的作用,并对近些年中药干预上述信号通路防治OS的国内外研究现状进行总结,旨在为今后深入研究中药治疗OS提供参考依据,以期为临床治疗OS提供新思路。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Aim Retinoic acid receptor alpha （RARα） plays a critical role in the differentiation process of osteo- sarcoma cells induced by all-trans retinoic acid （ATRA）. However, degradation of RARoL through ubiquitin pro- teasome pathway weakens the differentiation efficiency of osteosarcoma cells. Therefore, it is necessary to explore the regulatory mechanisms involved in RARoL degradation. Methods U2OS cells were mainly used as our research models. （1） Protein levels were detected by Western blot; （2） The interactions between MDM2 and RARalpha were determined by immunofluorescence and immunoprecipitation; （3） Related proteins and genes were investiga- ted via transfection; （4） The expression levels of MDM2 and OPN in patient biopsies were detected by immunohis- tochemistry; （5） Alkaline phosphatase activity was assessed by colorimetric assays using the BCIP/NBT Alkaline Phosphatase Color Development kit. Results In this report, it demonstrated that interaction with MDM2 leaded to strong stimulation of RARoL polyubiquitination and degradation by proteasomes. MDM2 appeared to function as an ubiquitin E3 ligase in this process, since the MDM2 RING domain mutant inhibited the ubiquitination of RARoL. Furthermore, MDM2 was capable of stimulating RARoL polyubiquitination under cell-free conditions. Moreover, it also provided evidence that silencing or inhibiting MDM2 promotes the differentiation of U2OS cells as induced by ATRA. Conclusions MDM2 serves as an E3 ubiquitin ligase to regulate the degradation of RARoL and becomes a novel therapeutic target for ATRA-based differentiation therapeutic approaches in osteosarcoma.
文摘Background and objective Osteosarcoma is a high-malignant bone tumor and is the most frequent malignant bone tumor in children and adolescents. Significant proportions of the
文摘骨肉瘤(osteosarcoma,OS)是最常见的原发性骨恶性肿瘤,具有很高的局部浸润和转移倾向。c-Jun氨基末端激酶(c-Jun N-terminal kinases,JNK)是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族中极为重要的一员,而且JNK信号通路已被证明参与调控了OS的发生发展。该文就JNK信号通路调控OS的增殖、迁移、侵袭、血管生成、自噬、凋亡和焦亡等生物学行为,以及氧化应激和非编码RNA通过JNK信号通路对OS调控的研究进展进行综述,进一步探究JNK信号通路的内在调控机制,为寻找OS的治疗提供新的思路。
文摘骨肉瘤(osteosarcoma,OS)是骨组织常见的原发性恶性肿瘤,具有较高的病死率、致残率、转移率和复发率,其发病机制复杂,严重影响患者的生活质量,给家庭和社会都带来了巨大的经济负担。中药具有“多靶点、多成分、多途径”的特点,近年来,大量动物或细胞模型实验研究发现,OS发生进展的作用机制与神经源性位点缺口同源蛋白(neurogenic locus notch homolog protein,Notch)、有丝分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、分泌型糖蛋白(Wingless/Integrated,Wnt)/β-连环蛋白(beta-catenin,β-catenin)、磷酸酰肌醇3-激酶(phosphatidylinositol-3-kinases,PI3K)/蛋白质激酶B(protein kinase B,AKT)、刺猬因子(Hedgehog,Hh)、核转录因子(nuclear factor kappa-B,NF-κB)、转化生长因子-β(transforming growth factor-β,TGF-β)/果蝇抗蜕皮蛋白同源物(small mothers against decapentaplegic,Smad)、信号转导及转录激活因子(signal transdueer and activator of tanseription,STAT)通路紧密相关,中药可通过干预以上相关信号通路从而影响细胞增殖、迁移、侵袭、凋亡和自噬等生物学过程发挥抗肿瘤的作用。本研究以细胞信号通路为基础,阐述了上述信号通路在OS中的作用,并对近些年中药干预上述信号通路防治OS的国内外研究现状进行总结,旨在为今后深入研究中药治疗OS提供参考依据,以期为临床治疗OS提供新思路。
