Background:Despite the identification of numerous therapeutic targets in lung cancer,achieving significant efficacy has been challenging.TNFRSF21 plays an important role in various cancers.We investigated the function...Background:Despite the identification of numerous therapeutic targets in lung cancer,achieving significant efficacy has been challenging.TNFRSF21 plays an important role in various cancers.We investigated the function of TNFRSF21 in lung adenocarcinoma(LUAD).Methods:The prognostic value of TNFRSF21 expression in lung cancer was evaluated by the GEPIA and Kaplan-Meier Plotter databases.Lung cancer cell viability was assessed by the CCK8 assay.TNFRSF21 expression patterns in lung cancer tissues and cells were examined using RT-PCR assay.Tumor sphere growth was evaluated through tumor sphere formation assays.MtROS contents in lung cancer cells were observed through MitoSOX fluorescent assays.Result:TNFRSF21 was up-regulated in LUAD patients.TNFRSF21 induction was particularly notable in LUAD,especially in cancerous cells(A549,H1299,H460,and SPC-A1),compared to BEAS-2B cells.Additionally,TNFRSF21 was increased in cisplatin(DDP)-resistant LUAD cells.Loss of TNFRSF21 significantly inhibited LUAD cell growth.It was observed that forced expression of TNFRSF21 contributed to tumor cell proliferation and DDP resistance.The production of ROS was found to participate in the inhibitory effects on lung cancer stem cells(CSCs),with decreased TNFRSF21 restraining ROS contents.Collectively,these findings reveal that the downregulation of TNFRSF21 promotes ROS contents to restrain the lung CSC-like characteristics via modulation of CD44 and CD133.Conclusions:In conclusion,TNFRSF21 may act as a novel target for lung cancer chemotherapy,particularly for eradicating lung CSCs.展开更多
目的:运用网络药理学和生物信息学技术探讨驻春胶囊治疗肾阳虚型骨质疏松症的作用机制。方法:使用中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)筛选驻春...目的:运用网络药理学和生物信息学技术探讨驻春胶囊治疗肾阳虚型骨质疏松症的作用机制。方法:使用中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)筛选驻春胶囊组方中药的活性成分,并使用TCMSP和Drugbank数据库检索有效成分相关靶点。在GeneCards数据库、药物靶标数据库(therapeutic target database,TTD)和人类在线孟德尔遗传数据库(online mendelian inheritance in man,OMIM)中检索骨质疏松症致病靶点;在GEO数据库中筛选肾阳虚型骨质疏松症患者与正常人之间的差异表达基因;将两者取交集,得到肾阳虚型骨质疏松症致病靶点。将活性成分相关靶点与肾阳虚型骨质疏松症致病靶点取交集,得到驻春胶囊治疗肾阳虚型骨质疏松症的潜在靶点。利用Cytoscape 3.9.1软件构建“药物-活性成分-潜在靶点”网络。利用R软件对潜在靶点进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopediaof genes and genome,KEGG)信号通路富集分析。采用STRING数据库进行聚类关联分析,并通过CytoNCA分析筛选驻春胶囊治疗肾阳虚型骨质疏松症的关键靶基因。采用AutodockVina软件对活性成分和关键靶基因进行分子对接验证;采用CIBERSORT进行免疫细胞浸润分析。结果:本研究共筛选得到183个活性成分、2732个活性成分相关靶点、897个肾阳虚型骨质疏松症的疾病靶点。将活性成分相关靶点与疾病靶点取交集,得到34个驻春胶囊治疗肾阳虚型骨质疏松症的潜在靶点。“药物-活性成分-潜在靶点”网络分析得到木犀草素、8-异戊烯-山柰酚(8-isopentenyl-kaempferol)、黄豆黄素(glycitein)、柚皮素(naringenin)、槲皮素(quercetin)等有效活性成分和SIRT1、CDKN1B、TNFRSF1A等潜在靶基因。GO和KEGG通路富集分析显示,主要靶点富集在多个细胞组分、生物过程及信号通路上。PPI网络分析得到SIRT1、CDKN1B和TNFRSF1A为驻春胶囊治疗肾阳虚型骨质疏松症的关键靶基因。分子对接显示活性成分与关键靶点对接良好。CIBERSORT免疫浸润分析显示,与正常对照组相比,肾阳虚型骨质疏松症组中激活的NK细胞和静止的Mast细胞显著降低,NK细胞的激活与TNFRSF1A的表达呈显著的负相关。结论:驻春胶囊的多个有效活性成分可能通过多个靶点激活多条信号通路发挥改善肾阳虚型骨质疏松症的作用,其中通过TNFRSF1A调控NK细胞的激活可能是驻春胶囊治疗肾阳虚型骨质疏松症的关键环节之一。展开更多
Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug r...Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.展开更多
基金supported by the Scientific Research Program of Science and Technology Bureau of Huai’an City(Grant No.HAB202119).
文摘Background:Despite the identification of numerous therapeutic targets in lung cancer,achieving significant efficacy has been challenging.TNFRSF21 plays an important role in various cancers.We investigated the function of TNFRSF21 in lung adenocarcinoma(LUAD).Methods:The prognostic value of TNFRSF21 expression in lung cancer was evaluated by the GEPIA and Kaplan-Meier Plotter databases.Lung cancer cell viability was assessed by the CCK8 assay.TNFRSF21 expression patterns in lung cancer tissues and cells were examined using RT-PCR assay.Tumor sphere growth was evaluated through tumor sphere formation assays.MtROS contents in lung cancer cells were observed through MitoSOX fluorescent assays.Result:TNFRSF21 was up-regulated in LUAD patients.TNFRSF21 induction was particularly notable in LUAD,especially in cancerous cells(A549,H1299,H460,and SPC-A1),compared to BEAS-2B cells.Additionally,TNFRSF21 was increased in cisplatin(DDP)-resistant LUAD cells.Loss of TNFRSF21 significantly inhibited LUAD cell growth.It was observed that forced expression of TNFRSF21 contributed to tumor cell proliferation and DDP resistance.The production of ROS was found to participate in the inhibitory effects on lung cancer stem cells(CSCs),with decreased TNFRSF21 restraining ROS contents.Collectively,these findings reveal that the downregulation of TNFRSF21 promotes ROS contents to restrain the lung CSC-like characteristics via modulation of CD44 and CD133.Conclusions:In conclusion,TNFRSF21 may act as a novel target for lung cancer chemotherapy,particularly for eradicating lung CSCs.
文摘目的:运用网络药理学和生物信息学技术探讨驻春胶囊治疗肾阳虚型骨质疏松症的作用机制。方法:使用中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)筛选驻春胶囊组方中药的活性成分,并使用TCMSP和Drugbank数据库检索有效成分相关靶点。在GeneCards数据库、药物靶标数据库(therapeutic target database,TTD)和人类在线孟德尔遗传数据库(online mendelian inheritance in man,OMIM)中检索骨质疏松症致病靶点;在GEO数据库中筛选肾阳虚型骨质疏松症患者与正常人之间的差异表达基因;将两者取交集,得到肾阳虚型骨质疏松症致病靶点。将活性成分相关靶点与肾阳虚型骨质疏松症致病靶点取交集,得到驻春胶囊治疗肾阳虚型骨质疏松症的潜在靶点。利用Cytoscape 3.9.1软件构建“药物-活性成分-潜在靶点”网络。利用R软件对潜在靶点进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopediaof genes and genome,KEGG)信号通路富集分析。采用STRING数据库进行聚类关联分析,并通过CytoNCA分析筛选驻春胶囊治疗肾阳虚型骨质疏松症的关键靶基因。采用AutodockVina软件对活性成分和关键靶基因进行分子对接验证;采用CIBERSORT进行免疫细胞浸润分析。结果:本研究共筛选得到183个活性成分、2732个活性成分相关靶点、897个肾阳虚型骨质疏松症的疾病靶点。将活性成分相关靶点与疾病靶点取交集,得到34个驻春胶囊治疗肾阳虚型骨质疏松症的潜在靶点。“药物-活性成分-潜在靶点”网络分析得到木犀草素、8-异戊烯-山柰酚(8-isopentenyl-kaempferol)、黄豆黄素(glycitein)、柚皮素(naringenin)、槲皮素(quercetin)等有效活性成分和SIRT1、CDKN1B、TNFRSF1A等潜在靶基因。GO和KEGG通路富集分析显示,主要靶点富集在多个细胞组分、生物过程及信号通路上。PPI网络分析得到SIRT1、CDKN1B和TNFRSF1A为驻春胶囊治疗肾阳虚型骨质疏松症的关键靶基因。分子对接显示活性成分与关键靶点对接良好。CIBERSORT免疫浸润分析显示,与正常对照组相比,肾阳虚型骨质疏松症组中激活的NK细胞和静止的Mast细胞显著降低,NK细胞的激活与TNFRSF1A的表达呈显著的负相关。结论:驻春胶囊的多个有效活性成分可能通过多个靶点激活多条信号通路发挥改善肾阳虚型骨质疏松症的作用,其中通过TNFRSF1A调控NK细胞的激活可能是驻春胶囊治疗肾阳虚型骨质疏松症的关键环节之一。
基金Research Projects-Joint Fund for Applied Basic Research of Kunming Medical University,Yunnan Provincial Department of Science and Technology(No.2018FE001(-113),No.202301AY070001-098)Open project of Yunnan Clinical Medical Center(Nos.2020LCZXKF-XY02,XY06,XY16+1 种基金2022LCZXKF-XY02)Yunnan Health Training Project of High Level Talents(No.D–2018018).
文摘Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.
