Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological fu...Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.Methods:First,we found that the expression of OTUB2 was upregulated in TNBC by bioinformatics analysis,we then validated its expression in TNBC tissues and cells using immunohistochemistry(IHC)and qPCR and plotted the survival curves by Kaplan-Meier method.Gene set enrichment analysis(GSEA)suggested that OTUB2 may be involved in tumor proliferation and metastasis.Further functional assays,including Cell Counting Kit-8(CCK-8),colony formation,Transwell,and wound healing assays,were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration.Additionally,UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.Results:Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis.Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells,while its knockdown inhibited these processes.Moreover,OTUB2 stabilized tumor necrosis factor receptor-associated factor 6(TRAF6)by deubiquitinating it,leading to activation of the protein kinase B(AKT)pathway.Conclusions:OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.展开更多
目的探讨Otubain2(OTUB2)、TAZ(含有WW结构域的转录调节因子1)在食管鳞癌(ESCC)中的表达及其临床意义。方法收集新疆医科大学第一附属医院病理科2008-2018年诊断的272例ESCC患者石蜡标本及临床病理资料进行回顾性分析。利用生物信息数...目的探讨Otubain2(OTUB2)、TAZ(含有WW结构域的转录调节因子1)在食管鳞癌(ESCC)中的表达及其临床意义。方法收集新疆医科大学第一附属医院病理科2008-2018年诊断的272例ESCC患者石蜡标本及临床病理资料进行回顾性分析。利用生物信息数据库分析OTUB2在食管癌中的表达情况及与TAZ的相互作用关系;采用免疫组织化学(SP)法检测OTUB2、TAZ在ESCC组织和癌旁组织中的表达,分析其表达变化与ESCC患者临床病理参数及预后的相关性。结果TCGA(The Cancer Genome Atlas)数据库检索分析发现,OTUB2在食管癌中表达显著高于正常食管癌旁组织;STRING数据库检索发现,OTUB2与TAZ存在相互作用关系;免疫组化结果显示,OTUB2蛋白在ESCC组织和癌旁组织中的阳性表达率分别为87.9%、12.1%,TAZ蛋白在ESCC组织和癌旁组织中的阳性表达率分别为85.9%、14.1%,差异均具有统计学意义(P<0.05);OTUB2蛋白表达水平与肿瘤大小、分化程度有关(P<0.05);TAZ蛋白表达水平与肿瘤大小、分化程度、浸润深度、TNM分期及淋巴结转移有关(P<0.05);OTUB2与TAZ在ESCC中的表达水平呈正相关(P=0.000,r=0.216);预后因素分析结果显示,OTUB2与TAZ表达情况、肿瘤大小、浸润深度、有无淋巴转移、与患者的预后均具有统计学意义(P<0.05),OTUB2与ESCC患者中TAZ高表达组的位总生存时间(OS)较低表达组更短(P<0.05)。结论OTUB2与TAZ的表达与ESCC的发展密切相关,有望为ESCC的治疗靶点提供新的参考。展开更多
Autoreactive CD8^(+)T cells play a key role in type 1 diabetes(T1D),but the antigen spectrum that activates autoreactive CD8^(+)T cells remains unclear.Endoplasmic reticulum stress(ERS)has been implicated inβ-cell au...Autoreactive CD8^(+)T cells play a key role in type 1 diabetes(T1D),but the antigen spectrum that activates autoreactive CD8^(+)T cells remains unclear.Endoplasmic reticulum stress(ERS)has been implicated inβ-cell autoantigen generation.Here,we analyzed the major histocompatibility complex class I(MHC-I)-associated immunopeptidome(MIP)of isletβ-cells under steady and ERS conditions and found that ERS reshaped the MIP ofβ-cells and promoted the MHC-I presentation of a panel of conventional self-peptides.Among them,OTUB2_(58-66 ) showed immunodominance,and the corresponding autoreactive CD8^(+)T cells were diabetogenic in nonobese diabetic(NOD)mice.High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB2_(58-66 )-specific CD8^(+)T-cell response in NOD mice.Repeated OTUB2_(58-66 )administration significantly reduced the incidence of T1D in NOD mice.Interestingly,peripheral blood mononuclear cells(PBMCs)from patients with T1D,but not from healthy controls,showed a positive IFN-γresponse to human OTUB2 peptides.This study provides not only a new explanation for the role of ERS in promotingβ-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D.The data are available via ProteomeXchange with the identifier PXD041227.展开更多
基金supported by the National Natural Science Foundation of China(No.82373380,Xinhua Xie).
文摘Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.Methods:First,we found that the expression of OTUB2 was upregulated in TNBC by bioinformatics analysis,we then validated its expression in TNBC tissues and cells using immunohistochemistry(IHC)and qPCR and plotted the survival curves by Kaplan-Meier method.Gene set enrichment analysis(GSEA)suggested that OTUB2 may be involved in tumor proliferation and metastasis.Further functional assays,including Cell Counting Kit-8(CCK-8),colony formation,Transwell,and wound healing assays,were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration.Additionally,UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.Results:Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis.Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells,while its knockdown inhibited these processes.Moreover,OTUB2 stabilized tumor necrosis factor receptor-associated factor 6(TRAF6)by deubiquitinating it,leading to activation of the protein kinase B(AKT)pathway.Conclusions:OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.
文摘目的探讨Otubain2(OTUB2)、TAZ(含有WW结构域的转录调节因子1)在食管鳞癌(ESCC)中的表达及其临床意义。方法收集新疆医科大学第一附属医院病理科2008-2018年诊断的272例ESCC患者石蜡标本及临床病理资料进行回顾性分析。利用生物信息数据库分析OTUB2在食管癌中的表达情况及与TAZ的相互作用关系;采用免疫组织化学(SP)法检测OTUB2、TAZ在ESCC组织和癌旁组织中的表达,分析其表达变化与ESCC患者临床病理参数及预后的相关性。结果TCGA(The Cancer Genome Atlas)数据库检索分析发现,OTUB2在食管癌中表达显著高于正常食管癌旁组织;STRING数据库检索发现,OTUB2与TAZ存在相互作用关系;免疫组化结果显示,OTUB2蛋白在ESCC组织和癌旁组织中的阳性表达率分别为87.9%、12.1%,TAZ蛋白在ESCC组织和癌旁组织中的阳性表达率分别为85.9%、14.1%,差异均具有统计学意义(P<0.05);OTUB2蛋白表达水平与肿瘤大小、分化程度有关(P<0.05);TAZ蛋白表达水平与肿瘤大小、分化程度、浸润深度、TNM分期及淋巴结转移有关(P<0.05);OTUB2与TAZ在ESCC中的表达水平呈正相关(P=0.000,r=0.216);预后因素分析结果显示,OTUB2与TAZ表达情况、肿瘤大小、浸润深度、有无淋巴转移、与患者的预后均具有统计学意义(P<0.05),OTUB2与ESCC患者中TAZ高表达组的位总生存时间(OS)较低表达组更短(P<0.05)。结论OTUB2与TAZ的表达与ESCC的发展密切相关,有望为ESCC的治疗靶点提供新的参考。
基金National Natural Science Foundation of China(No.82071825 and No.81871301)National Key Research and Development Program(No.2016YFA0502204)Shandong Provincial Natural Science Fund(ZR2023MH201).
文摘Autoreactive CD8^(+)T cells play a key role in type 1 diabetes(T1D),but the antigen spectrum that activates autoreactive CD8^(+)T cells remains unclear.Endoplasmic reticulum stress(ERS)has been implicated inβ-cell autoantigen generation.Here,we analyzed the major histocompatibility complex class I(MHC-I)-associated immunopeptidome(MIP)of isletβ-cells under steady and ERS conditions and found that ERS reshaped the MIP ofβ-cells and promoted the MHC-I presentation of a panel of conventional self-peptides.Among them,OTUB2_(58-66 ) showed immunodominance,and the corresponding autoreactive CD8^(+)T cells were diabetogenic in nonobese diabetic(NOD)mice.High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB2_(58-66 )-specific CD8^(+)T-cell response in NOD mice.Repeated OTUB2_(58-66 )administration significantly reduced the incidence of T1D in NOD mice.Interestingly,peripheral blood mononuclear cells(PBMCs)from patients with T1D,but not from healthy controls,showed a positive IFN-γresponse to human OTUB2 peptides.This study provides not only a new explanation for the role of ERS in promotingβ-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D.The data are available via ProteomeXchange with the identifier PXD041227.
