目的:检测E-钙黏蛋白及β-连环蛋白在乳房外Paget病(extramammary Paget s disease,EMPD)中的表达情况,分析其在EMPD中侵袭及转移的作用。方法:收集2010年1月至2018年10月确诊的EMPD患者皮损组织标本,对照标本为包皮环切术切除的正常包...目的:检测E-钙黏蛋白及β-连环蛋白在乳房外Paget病(extramammary Paget s disease,EMPD)中的表达情况,分析其在EMPD中侵袭及转移的作用。方法:收集2010年1月至2018年10月确诊的EMPD患者皮损组织标本,对照标本为包皮环切术切除的正常包皮,应用免疫组织化学方法检测两组标本中E-钙黏蛋白和β-连环蛋白的表达,以染色强度和染色百分率的评分之积进行结果判定。结果:共收集33例EMPD皮损组织标本及25块对照标本。免疫组化结果示E-钙黏蛋白与β-连环蛋白阳性表达主要位于细胞膜上。EMPD患者病理组织中E-钙黏蛋白和β-连环蛋白的强阳性表达率分别为0%和3.0%,阳性表达率分别为36.4%和54.5%,弱阳性表达率分别为51.5%和24.2%,阴性表达率分别为12.1%和18.2%,正常组织E-钙黏蛋白与β-连环蛋白表达全部为强阳性表达。两组标本间E-钙黏蛋白和β-连环蛋白表达差异均具有统计学意义(均P<0.05);E-钙黏蛋白的表达与EMPD患者的年龄、性别、发病部位及淋巴结转移无显著相关性(均P>0.05),与发生真皮浸润有显著相关性(P<0.05);E-钙黏蛋白与β-连环蛋白表达呈正相关(r=0.490,P<0.01)。结论:E-钙粘蛋白及β-连环蛋白在EMPD中的表达是协同作用。E-钙黏蛋白表达的下调可能与EMPD肿瘤发生侵袭具有相关性,但与EMPD肿瘤转移可能无关。展开更多
Paget’s disease(PDB)is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications.One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene.Although the geneti...Paget’s disease(PDB)is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications.One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene.Although the genetic involvement of ZNF687 in PDB has been extensively studied,the molecular mechanisms underlying this association remain unclear.Here,we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype,resulting in severely altered bone remodeling.Through microcomputed tomography analysis,we observed that 8-month-old mutant mice showed a mainly osteolytic phase,with a significant decrease in the trabecular bone volume affecting the femurs and the vertebrae.Conversely,osteoblast activity was deregulated,producing disorganized bone.Notably,this phenotype became pervasive in 16-month-old mice,where osteoblast function overtook bone resorption,as highlighted by the presence of woven bone in histological analyses,consistent with the PDB phenotype.Furthermore,we detected osteophytes and intervertebral disc degeneration,outlining for the first time the link between osteoarthritis and PDB in a PDB mouse model.RNA sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687,e.g.,Tspan7,Cpe,Vegfc,and Ggt1,confirming its role in this process.Strikingly,in this mouse model,the mutation was also associated with a high penetrance of hepatocellular carcinomas.Thus,this study established an essential role of Zfp687 in the regulation of bone remodeling,offering the potential to therapeutically treat PDB,and underlines the oncogenic potential of ZNF687.展开更多
文摘目的:检测E-钙黏蛋白及β-连环蛋白在乳房外Paget病(extramammary Paget s disease,EMPD)中的表达情况,分析其在EMPD中侵袭及转移的作用。方法:收集2010年1月至2018年10月确诊的EMPD患者皮损组织标本,对照标本为包皮环切术切除的正常包皮,应用免疫组织化学方法检测两组标本中E-钙黏蛋白和β-连环蛋白的表达,以染色强度和染色百分率的评分之积进行结果判定。结果:共收集33例EMPD皮损组织标本及25块对照标本。免疫组化结果示E-钙黏蛋白与β-连环蛋白阳性表达主要位于细胞膜上。EMPD患者病理组织中E-钙黏蛋白和β-连环蛋白的强阳性表达率分别为0%和3.0%,阳性表达率分别为36.4%和54.5%,弱阳性表达率分别为51.5%和24.2%,阴性表达率分别为12.1%和18.2%,正常组织E-钙黏蛋白与β-连环蛋白表达全部为强阳性表达。两组标本间E-钙黏蛋白和β-连环蛋白表达差异均具有统计学意义(均P<0.05);E-钙黏蛋白的表达与EMPD患者的年龄、性别、发病部位及淋巴结转移无显著相关性(均P>0.05),与发生真皮浸润有显著相关性(P<0.05);E-钙黏蛋白与β-连环蛋白表达呈正相关(r=0.490,P<0.01)。结论:E-钙粘蛋白及β-连环蛋白在EMPD中的表达是协同作用。E-钙黏蛋白表达的下调可能与EMPD肿瘤发生侵袭具有相关性,但与EMPD肿瘤转移可能无关。
基金Italian Association for Cancer Research(AIRC)under IG 2020-ID.25110 projectPOR Campania FESR 2014/2020(Project SATIN)+1 种基金Progetto MISE(F/050011/02/X32)–P.I.Fernando Gianfrancescofunding from the European Calcified Tissue Society(ECTS)and the Italian Society for Osteoporosis,Mineral Metabolism and Skeletal Diseases(SIOMMMS)。
文摘Paget’s disease(PDB)is a late-onset bone remodeling disorder with a broad spectrum of symptoms and complications.One of the most aggressive forms is caused by the P937R mutation in the ZNF687 gene.Although the genetic involvement of ZNF687 in PDB has been extensively studied,the molecular mechanisms underlying this association remain unclear.Here,we describe the first Zfp687 knock-in mouse model and demonstrate that the mutation recapitulates the PDB phenotype,resulting in severely altered bone remodeling.Through microcomputed tomography analysis,we observed that 8-month-old mutant mice showed a mainly osteolytic phase,with a significant decrease in the trabecular bone volume affecting the femurs and the vertebrae.Conversely,osteoblast activity was deregulated,producing disorganized bone.Notably,this phenotype became pervasive in 16-month-old mice,where osteoblast function overtook bone resorption,as highlighted by the presence of woven bone in histological analyses,consistent with the PDB phenotype.Furthermore,we detected osteophytes and intervertebral disc degeneration,outlining for the first time the link between osteoarthritis and PDB in a PDB mouse model.RNA sequencing of wild-type and Zfp687 knockout RAW264.7 cells identified a set of genes involved in osteoclastogenesis potentially regulated by Zfp687,e.g.,Tspan7,Cpe,Vegfc,and Ggt1,confirming its role in this process.Strikingly,in this mouse model,the mutation was also associated with a high penetrance of hepatocellular carcinomas.Thus,this study established an essential role of Zfp687 in the regulation of bone remodeling,offering the potential to therapeutically treat PDB,and underlines the oncogenic potential of ZNF687.
