目的基于淀粉样β前体蛋白(amyloid beta precursor protein,APP)家族、淀粉样β前体蛋白结合蛋白A(amyloid beta precursor protein binding family A,APBA)家族和淀粉样β前体蛋白结合蛋白B(amyloid beta precursor protein binding f...目的基于淀粉样β前体蛋白(amyloid beta precursor protein,APP)家族、淀粉样β前体蛋白结合蛋白A(amyloid beta precursor protein binding family A,APBA)家族和淀粉样β前体蛋白结合蛋白B(amyloid beta precursor protein binding family B,APBB)家族构建胃癌预后评估模型。方法从基因表达综合(gene expression omnibus,GEO)数据库下载GSE62254胃癌数据集作为训练集,GSE15459作为验证集。利用Cox回归分析筛选APP家族、APBA家族和APBB家族中胃癌预后的独立危险因素;分别建立基于三家族独立预后因素的风险评分1(risk score 1,RS1)、RS1联合病理学参数的RS2、传统TNM分期的RS3;卡方检验分析RS1与胃癌患者临床病理特征的关系;利用单细胞在线分析网站,分析纳入RS1模型的基因在不同细胞亚群中的表达情况;利用CIBERSORT分析RS1对不同免疫细胞浸润的影响;利用基因集富集分析(gene set enrichment analysis,GSEA)进行通路富集分析。结果APLP2、APBB1、APBB2是胃癌患者预后的独立危险因素(P<0.05),基于三者的风险评分RS1高组患者生存期明显短于RS1低组患者。联合临床病理学参数的Cox回归分析显示,N分期、M分期、Lauren分型和RS1是胃癌患者预后的独立危险因素(P<0.05)。基于此构建的RS2(AUC=0.767)比仅基于T分期、N分期、M分期构建的RS3(AUC=0.719)预测准确率提高了4.8%。RS1和肿瘤T分期呈正相关(P<0.05),RS1高组CD4静息细胞浸润较高,激活细胞浸润较低,M2巨噬细胞浸润较高。GSEA通路分析显示,高RS1组患者富集于MAPK、MTOR和WNT等通路。结论本研究成功构建了基于APP、APBA和APBB家族的胃癌预后评估模型,该模型能够较准确地判断胃癌患者预后。展开更多
Spermatogonial stem cells(SSCs)are essential for initiating and maintaining normal spermatogenesis,and notably,they have important applications in both reproduction and regenerative medicine.Nevertheless,the molecular...Spermatogonial stem cells(SSCs)are essential for initiating and maintaining normal spermatogenesis,and notably,they have important applications in both reproduction and regenerative medicine.Nevertheless,the molecular mechanisms controlling the fate determinations of human SSCs remain elusive.In this study,we identified a selective expression of APBB1 in dormant human SSCs.We demonstrated for the first time that APBB1 interacted with KAT5,which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation.Intriguingly,Apbb1^(-/-)mice assumed the disrupted spermatogenesis and markedly reduced fertility.SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation,which resulted in the impaired spermatogenesis.Notably,4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia(NOA),and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1^(-/-)mice.Additionally,we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis.Collectively,our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.展开更多
文摘目的基于淀粉样β前体蛋白(amyloid beta precursor protein,APP)家族、淀粉样β前体蛋白结合蛋白A(amyloid beta precursor protein binding family A,APBA)家族和淀粉样β前体蛋白结合蛋白B(amyloid beta precursor protein binding family B,APBB)家族构建胃癌预后评估模型。方法从基因表达综合(gene expression omnibus,GEO)数据库下载GSE62254胃癌数据集作为训练集,GSE15459作为验证集。利用Cox回归分析筛选APP家族、APBA家族和APBB家族中胃癌预后的独立危险因素;分别建立基于三家族独立预后因素的风险评分1(risk score 1,RS1)、RS1联合病理学参数的RS2、传统TNM分期的RS3;卡方检验分析RS1与胃癌患者临床病理特征的关系;利用单细胞在线分析网站,分析纳入RS1模型的基因在不同细胞亚群中的表达情况;利用CIBERSORT分析RS1对不同免疫细胞浸润的影响;利用基因集富集分析(gene set enrichment analysis,GSEA)进行通路富集分析。结果APLP2、APBB1、APBB2是胃癌患者预后的独立危险因素(P<0.05),基于三者的风险评分RS1高组患者生存期明显短于RS1低组患者。联合临床病理学参数的Cox回归分析显示,N分期、M分期、Lauren分型和RS1是胃癌患者预后的独立危险因素(P<0.05)。基于此构建的RS2(AUC=0.767)比仅基于T分期、N分期、M分期构建的RS3(AUC=0.719)预测准确率提高了4.8%。RS1和肿瘤T分期呈正相关(P<0.05),RS1高组CD4静息细胞浸润较高,激活细胞浸润较低,M2巨噬细胞浸润较高。GSEA通路分析显示,高RS1组患者富集于MAPK、MTOR和WNT等通路。结论本研究成功构建了基于APP、APBA和APBB家族的胃癌预后评估模型,该模型能够较准确地判断胃癌患者预后。
基金supported by grants from the National Natural Science Foundation of China(nos.82201771,32270912,and 32170862)Natural Science Foundation of Hunan Province(nos.2024JJ6083 and 2023JJ31018)+4 种基金Health Research Project of Hunan Provincial Health Commission(nos.W20243143 and 20231769)Natural Science Foundation of Changsha(nos.kq2202491 and kq2502312)Science and Technology Innovation Project of Hunan Province(no.2021SK53204)Clinical Medical Technology Demonstration Base for Genetic Research of Fetal Congenital Heart Disease in Hunan Province(no.2021SK4036)Hunan Province Children’s Safe Medication Clinical Medical Technology Demonstration Base(no.2023SK4083).
文摘Spermatogonial stem cells(SSCs)are essential for initiating and maintaining normal spermatogenesis,and notably,they have important applications in both reproduction and regenerative medicine.Nevertheless,the molecular mechanisms controlling the fate determinations of human SSCs remain elusive.In this study,we identified a selective expression of APBB1 in dormant human SSCs.We demonstrated for the first time that APBB1 interacted with KAT5,which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation.Intriguingly,Apbb1^(-/-)mice assumed the disrupted spermatogenesis and markedly reduced fertility.SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation,which resulted in the impaired spermatogenesis.Notably,4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia(NOA),and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1^(-/-)mice.Additionally,we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis.Collectively,our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.
