目的:探讨微小RNA-296-5p、S期激酶相关蛋白2(S-phase kinase-associated protein 2,Skp2)、核糖体蛋白L6(ribosomal protein L6,RPL6)与前列腺癌病理特征的关系及对手术预后的影响。方法:选取2018年1月至2023年1月120例前列腺患者,均...目的:探讨微小RNA-296-5p、S期激酶相关蛋白2(S-phase kinase-associated protein 2,Skp2)、核糖体蛋白L6(ribosomal protein L6,RPL6)与前列腺癌病理特征的关系及对手术预后的影响。方法:选取2018年1月至2023年1月120例前列腺患者,均行腹腔镜前列腺癌术治疗,对比不同病理特征患者miR-296-5p、Skp2、RPL6 mRNA表达水平,分析各指标与病理特征的关系。根据术后1年是否生化复发分为复发组(n=21)与未复发组(n=97),比较2组临床资料、miR-296-5p、Skp2、RPL6mRNA表达水平,分析miR-296-5p、Skp2、RPL6对手术预后的影响及预测价值。结果:不同病理分期、Gleason评分、术前血清前列腺特异性抗原(prostate specific antigen,PSA)水平、淋巴结转移患者miR-296-5p、Skp2、RPL6 mRNA表达水平比较,差异有统计学意义(F=12.927、22.416、10.088、34.239、20.180、12.208,t=4.649、-5.770、-5.713、4.716、-5.647、-6.884,均P=0.000);miR-296-5p与Gleason评分、病理分期、术前血清前列腺特异性抗原(prostate specific antigen,PSA)水平、淋巴结转移呈负相关(r=-0.578、-0.539、-0.517、-0.556,均P<0.001),Skp2、RPL6 mRNA与Gleason评分、病理分期、术前血清PSA水平、淋巴结转移呈正相关(r=0.531、0.507、0.476、0.493、0.494、0.473、0.420、0.505,均P<0.001);复发组淋巴结转移、病理分期、切缘阳性率、Gleason评分、高于未复发组,术后辅助治疗率低于未复发组(P<0.05);复发组miR-296-5p表达水平低于未复发组,Skp2、RPL6mRNA表达水平高于未复发组(P<0.05);校正前,logistic回归分析,病理分期、Gleason评分、淋巴结转移、切缘阳性、术后辅助治疗、miR-296-5p、Skp2、RPL6 mRNA是前列腺癌患者术后生化复发的影响因素(P<0.05),校正后,miR-296-5p、Skp2、RPL6mRNA仍是前列腺癌患者术后生化复发的影响因素(P<0.05);miR-296-5p、Skp2、RPL6联合预测前列腺术后生化复发的AUC为0.902(95%CI=0.833~0.949),大于各指标单独预测(P<0.05)。结论:前列腺癌患者miR-296-5p、Skp2、RPL6表达水平与病理特征、术后复发密切相关,三者联合预测前列腺术后生化复发具有较高的参考价值。展开更多
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal...TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain geno...The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain genomic stability remain unclear.Also,recent studies have uncovered noncanonical roles of ribosome-associated factors in maintaining genomic stability.In this study,somatic skin fibroblasts from the long-lived big-footed bat(Myotis pilosus)were examined,with results showing that bat cells exhibited enhanced RS tolerance compared to mouse cells.Comparative transcriptome analysis under RS conditions revealed pronounced species-specific transcriptional differences,including robust up-regulation of ribosome biogenesis genes in bat cells and a markedly reduced activation of the P53 signaling pathway.These features emphasize a distinct homeostatic strategy in bat cells.Nuclear fragile X mental retardation-interacting protein 1(Nufip1),a ribosome-associated factor highly expressed in bat fibroblasts,was identified as a potential integrator of ribosomal and P53 signaling via its association with ribosomal protein S27-like(Rps27l).These findings provide direct cellular and molecular evidence for a noncanonical RS response in bats,highlighting a deeper understanding of the biological characteristics and genomic maintenance mechanisms of long-lived species.展开更多
To investigate the histological,immunohistochemical,and molecular characteristics of sclerosing epithelioid fibrosarcoma(SEF),a rare intracranial lesion,we analyzed the clinical,pathological,and molecular features of ...To investigate the histological,immunohistochemical,and molecular characteristics of sclerosing epithelioid fibrosarcoma(SEF),a rare intracranial lesion,we analyzed the clinical,pathological,and molecular features of a group of cases involving both intracranial(case 1)and extracranial(cases 2,3,and 4)soft tissue tumors.These tumors were located in the bilateral parietal sinuses(one of four cases;25%),thoracic vertebrae(1 of 4 cases;25%),mediastinum(1 of 4 cases;25%),and parathyroid soft tissue(1 of 4 cases;25%).Microscopically,tumor cells were observed in both sparse and dense areas,arranged in sheets,cords,and a fusiform braided pattern,all within a dense sclerotic matrix.All four patients exhibited strong and diffuse positivity for MUC4.Cases 1 and 2 harbored an EWSR1–CREB3L1 fusion;case 3 had a CPSF6–ITPR2 fusion;and case 4 exhibited multiple fusion genes,including FUS–CREB3L2,KDM5A–ERC1,AKAP8L–BRD4,and ATF2–CHN1.Methylation analysis indicated that all cases clustered within the SEF spectrum.Copy number variation analysis revealed deletions in chromosomal arms 11p and 22q across all cases.The morphologies of intracranial and extracranial SEF were found to be similar.Although MUC4 serves as a reliable marker for diagnosing SEF,its molecular findings remain nonspecific.Methylation clustering and aneuploidy score assessment should be considered as additional tools to assist in diagnosis and prognostic monitoring.展开更多
文摘目的:探讨微小RNA-296-5p、S期激酶相关蛋白2(S-phase kinase-associated protein 2,Skp2)、核糖体蛋白L6(ribosomal protein L6,RPL6)与前列腺癌病理特征的关系及对手术预后的影响。方法:选取2018年1月至2023年1月120例前列腺患者,均行腹腔镜前列腺癌术治疗,对比不同病理特征患者miR-296-5p、Skp2、RPL6 mRNA表达水平,分析各指标与病理特征的关系。根据术后1年是否生化复发分为复发组(n=21)与未复发组(n=97),比较2组临床资料、miR-296-5p、Skp2、RPL6mRNA表达水平,分析miR-296-5p、Skp2、RPL6对手术预后的影响及预测价值。结果:不同病理分期、Gleason评分、术前血清前列腺特异性抗原(prostate specific antigen,PSA)水平、淋巴结转移患者miR-296-5p、Skp2、RPL6 mRNA表达水平比较,差异有统计学意义(F=12.927、22.416、10.088、34.239、20.180、12.208,t=4.649、-5.770、-5.713、4.716、-5.647、-6.884,均P=0.000);miR-296-5p与Gleason评分、病理分期、术前血清前列腺特异性抗原(prostate specific antigen,PSA)水平、淋巴结转移呈负相关(r=-0.578、-0.539、-0.517、-0.556,均P<0.001),Skp2、RPL6 mRNA与Gleason评分、病理分期、术前血清PSA水平、淋巴结转移呈正相关(r=0.531、0.507、0.476、0.493、0.494、0.473、0.420、0.505,均P<0.001);复发组淋巴结转移、病理分期、切缘阳性率、Gleason评分、高于未复发组,术后辅助治疗率低于未复发组(P<0.05);复发组miR-296-5p表达水平低于未复发组,Skp2、RPL6mRNA表达水平高于未复发组(P<0.05);校正前,logistic回归分析,病理分期、Gleason评分、淋巴结转移、切缘阳性、术后辅助治疗、miR-296-5p、Skp2、RPL6 mRNA是前列腺癌患者术后生化复发的影响因素(P<0.05),校正后,miR-296-5p、Skp2、RPL6mRNA仍是前列腺癌患者术后生化复发的影响因素(P<0.05);miR-296-5p、Skp2、RPL6联合预测前列腺术后生化复发的AUC为0.902(95%CI=0.833~0.949),大于各指标单独预测(P<0.05)。结论:前列腺癌患者miR-296-5p、Skp2、RPL6表达水平与病理特征、术后复发密切相关,三者联合预测前列腺术后生化复发具有较高的参考价值。
基金supported by the Koeln Fortune Program/Faculty of Medicine,University of Cologne,the Alzheimer Forschung Initiative e.V.(grant#22039,to HZ)open-access funding from the DFG/GRC issued to the University of CologneAlzheimer Forschung Initiative e.V.for Open Access Publishing(a publication grant#P2401,to MAAK)。
文摘TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
基金supported by the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(202401AT070186 to K.Q.L.,202201AS070044 to B.Z.)Yunnan Province(202305AH340006 to B.Z.)Kunming Science and Technology Bureau(2022SCP007 to B.Z.)。
文摘The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain genomic stability remain unclear.Also,recent studies have uncovered noncanonical roles of ribosome-associated factors in maintaining genomic stability.In this study,somatic skin fibroblasts from the long-lived big-footed bat(Myotis pilosus)were examined,with results showing that bat cells exhibited enhanced RS tolerance compared to mouse cells.Comparative transcriptome analysis under RS conditions revealed pronounced species-specific transcriptional differences,including robust up-regulation of ribosome biogenesis genes in bat cells and a markedly reduced activation of the P53 signaling pathway.These features emphasize a distinct homeostatic strategy in bat cells.Nuclear fragile X mental retardation-interacting protein 1(Nufip1),a ribosome-associated factor highly expressed in bat fibroblasts,was identified as a potential integrator of ribosomal and P53 signaling via its association with ribosomal protein S27-like(Rps27l).These findings provide direct cellular and molecular evidence for a noncanonical RS response in bats,highlighting a deeper understanding of the biological characteristics and genomic maintenance mechanisms of long-lived species.
基金supported by grants from the National Natural Science Foundation of China(No.82273082)Chongqing Technical Innovation and Application Development Key Project(No.cstc2021jscx-cylhX0005)。
文摘To investigate the histological,immunohistochemical,and molecular characteristics of sclerosing epithelioid fibrosarcoma(SEF),a rare intracranial lesion,we analyzed the clinical,pathological,and molecular features of a group of cases involving both intracranial(case 1)and extracranial(cases 2,3,and 4)soft tissue tumors.These tumors were located in the bilateral parietal sinuses(one of four cases;25%),thoracic vertebrae(1 of 4 cases;25%),mediastinum(1 of 4 cases;25%),and parathyroid soft tissue(1 of 4 cases;25%).Microscopically,tumor cells were observed in both sparse and dense areas,arranged in sheets,cords,and a fusiform braided pattern,all within a dense sclerotic matrix.All four patients exhibited strong and diffuse positivity for MUC4.Cases 1 and 2 harbored an EWSR1–CREB3L1 fusion;case 3 had a CPSF6–ITPR2 fusion;and case 4 exhibited multiple fusion genes,including FUS–CREB3L2,KDM5A–ERC1,AKAP8L–BRD4,and ATF2–CHN1.Methylation analysis indicated that all cases clustered within the SEF spectrum.Copy number variation analysis revealed deletions in chromosomal arms 11p and 22q across all cases.The morphologies of intracranial and extracranial SEF were found to be similar.Although MUC4 serves as a reliable marker for diagnosing SEF,its molecular findings remain nonspecific.Methylation clustering and aneuploidy score assessment should be considered as additional tools to assist in diagnosis and prognostic monitoring.
